{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:36:46Z","timestamp":1791380206322,"version":"4.3.3"},"reference-count":122,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T00:00:00Z","timestamp":1747612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Microbiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Of 250 <jats:italic>Plasmodium<\/jats:italic> species, 6 infect humans, with <jats:italic>P.<\/jats:italic>\u2009<jats:italic>falciparum<\/jats:italic> causing over 95% of 600,000 annual malaria-related deaths. Its pathology arises from host cell remodelling driven by over 400 exported parasite proteins, including the FIKK kinase family. About one million years ago, a bird-infecting <jats:italic>Plasmodium<\/jats:italic> species crossed into great apes and a single non-exported FIKK kinase gained an export element. This led to a rapid expansion into 15\u201321 atypical, exported Ser\/Thr effector kinases. Here, using genomic and proteomic analyses, we demonstrate FIKK differentiation via changes in subcellular localization, expression timing and substrate motifs, which supports an individual important role in host\u2013pathogen interactions. Structural data and AlphaFold2 predictions reveal fast-evolving loops in the kinase domain that probably enabled rapid functional diversification for substrate preferences. One FIKK evolved exclusive tyrosine phosphorylation, previously thought absent in <jats:italic>Plasmodium<\/jats:italic>. Despite divergence of substrate preferences, the atypical ATP binding pocket is conserved and we identified a single compound that inhibits all FIKKs. A pan-specific inhibitor could reduce resistance development and improve malaria control strategies.<\/jats:p>","DOI":"10.1038\/s41564-025-02017-4","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T09:02:38Z","timestamp":1747645358000},"page":"1463-1483","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound"],"prefix":"10.1038","volume":"10","author":[{"given":"Hugo","family":"Belda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8464-1558","authenticated-orcid":false,"given":"Evangelos","family":"Christodoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1415-3369","authenticated-orcid":false,"given":"Stephanie D.","family":"Nofal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Broncel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4789-203X","authenticated-orcid":false,"given":"David","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heledd","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-0903","authenticated-orcid":false,"given":"M. Teresa","family":"Bertran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Purkiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roksana W.","family":"Ogrodowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8660-2528","authenticated-orcid":false,"given":"Dhira","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4204-6491","authenticated-orcid":false,"given":"Nicola","family":"O\u2019Reilly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Walport","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1540-537X","authenticated-orcid":false,"given":"Andrew","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9635-2451","authenticated-orcid":false,"given":"David","family":"House","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9767-8683","authenticated-orcid":false,"given":"Svend","family":"Kjaer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4277-0914","authenticated-orcid":false,"given":"Antoine","family":"Claessens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-6866","authenticated-orcid":false,"given":"Christian R.","family":"Landry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7883-6743","authenticated-orcid":false,"given":"Moritz","family":"Treeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"2017_CR1","unstructured":"World Malaria Report 2023 (World Health Organization, 2023)."},{"key":"2017_CR2","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2006-7-2-r12","volume":"7","author":"TJ Sargeant","year":"2006","unstructured":"Sargeant, T. J. et al. Lineage-specific expansion of proteins exported to erythrocytes in malaria parasites. Genome Biol. 7, R12 (2006).","journal-title":"Genome Biol."},{"key":"2017_CR3","doi-asserted-by":"publisher","unstructured":"Warncke, J. D. & Beck, H. P. Host cytoskeleton remodeling throughout the blood stages of Plasmodium falciparum. Microbiol. Mol. Biol. Rev. https:\/\/doi.org\/10.1128\/MMBR.00013-19 (2019).","DOI":"10.1128\/MMBR.00013-19"},{"key":"2017_CR4","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0092-8674(95)90055-1","volume":"82","author":"XZ Su","year":"1995","unstructured":"Su, X. Z. et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes. Cell 82, 89\u2013100 (1995).","journal-title":"Cell"},{"key":"2017_CR5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0092-8674(95)90054-3","volume":"82","author":"DI Baruch","year":"1995","unstructured":"Baruch, D. I. et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes. Cell 82, 77\u201387 (1995).","journal-title":"Cell"},{"key":"2017_CR6","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.cell.2011.05.002","volume":"145","author":"W Nguitragool","year":"2011","unstructured":"Nguitragool, W. et al. Malaria parasite clag3 genes determine channel-mediated nutrient uptake by infected red blood cells. Cell 145, 665\u2013677 (2011).","journal-title":"Cell"},{"key":"2017_CR7","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1124\/mol.112.081224","volume":"82","author":"AD Pillai","year":"2012","unstructured":"Pillai, A. D. et al. Solute restriction reveals an essential role for clag3-associated channels in malaria parasite nutrient acquisition. Mol. Pharmacol. 82, 1104\u20131114 (2012).","journal-title":"Mol. Pharmacol."},{"key":"2017_CR8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.ijpara.2005.10.001","volume":"36","author":"M Lanzer","year":"2006","unstructured":"Lanzer, M., Wickert, H., Krohne, G., Vincensini, L. & Braun Breton, C. Maurer\u2019s clefts: a novel multi-functional organelle in the cytoplasm of Plasmodium falciparum-infected erythrocytes. Int J. Parasitol. 36, 23\u201336 (2006).","journal-title":"Int J. Parasitol."},{"key":"2017_CR9","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2164-5-79","volume":"5","author":"P Ward","year":"2004","unstructured":"Ward, P., Equinet, L., Packer, J. & Doerig, C. Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics 5, 79 (2004).","journal-title":"BMC Genomics"},{"key":"2017_CR10","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.chom.2010.09.006","volume":"8","author":"R Tewari","year":"2010","unstructured":"Tewari, R. et al. The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission. Cell Host Microbe 8, 377\u2013387 (2010).","journal-title":"Cell Host Microbe"},{"key":"2017_CR11","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1038\/nrmicro.2016.109","volume":"14","author":"WR Proto","year":"2016","unstructured":"Proto, W. R. Unravelling the Laverania. Nat. Rev. Microbiol. 14, 478 (2016).","journal-title":"Nat. Rev. Microbiol."},{"key":"2017_CR12","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11078","volume":"7","author":"SA Sundararaman","year":"2016","unstructured":"Sundararaman, S. A. et al. Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria. Nat. Commun. 7, 11078 (2016).","journal-title":"Nat. Commun."},{"key":"2017_CR13","doi-asserted-by":"crossref","first-page":"D539","DOI":"10.1093\/nar\/gkn814","volume":"37","author":"C Aurrecoechea","year":"2009","unstructured":"Aurrecoechea, C. et al. PlasmoDB: a functional genomic database for malaria parasites. Nucleic Acids Res. 37, D539\u2013D543 (2009).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR14","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41564-018-0162-2","volume":"3","author":"TD Otto","year":"2018","unstructured":"Otto, T. D. et al. Genomes of all known members of a Plasmodium subgenus reveal paths to virulent human malaria. Nat. Microbiol 3, 687\u2013697 (2018).","journal-title":"Nat. Microbiol"},{"key":"2017_CR15","doi-asserted-by":"crossref","first-page":"D898","DOI":"10.1093\/nar\/gkab929","volume":"50","author":"B Amos","year":"2022","unstructured":"Amos, B. et al. VEuPathDB: the eukaryotic pathogen, vector and host bioinformatics resource center. Nucleic Acids Res. 50, D898\u2013D911 (2022).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR16","doi-asserted-by":"publisher","unstructured":"Davies, H. et al. An exported kinase family mediates species-specific erythrocyte remodelling and virulence in human malaria. Nat. Microbiol. https:\/\/doi.org\/10.1038\/s41564-020-0702-4 (2020).","DOI":"10.1038\/s41564-020-0702-4"},{"key":"2017_CR17","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.ijpara.2014.01.003","volume":"44","author":"LM Kats","year":"2014","unstructured":"Kats, L. M. et al. An exported kinase (FIKK4.2) that mediates virulence-associated changes in Plasmodium falciparum-infected red blood cells. Int J. Parasitol. 44, 319\u2013328 (2014).","journal-title":"Int J. Parasitol."},{"key":"2017_CR18","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1126\/science.3291115","volume":"241","author":"SK Hanks","year":"1988","unstructured":"Hanks, S. K., Quinn, A. M. & Hunter, T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241, 42\u201352 (1988).","journal-title":"Science"},{"key":"2017_CR19","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1365-2958.2006.05521.x","volume":"63","author":"MC Nunes","year":"2007","unstructured":"Nunes, M. C., Goldring, J. P., Doerig, C. & Scherf, A. A novel protein kinase family in Plasmodium falciparum is differentially transcribed and secreted to various cellular compartments of the host cell. Mol. Microbiol. 63, 391\u2013403 (2007).","journal-title":"Mol. Microbiol."},{"key":"2017_CR20","doi-asserted-by":"crossref","first-page":"e11747","DOI":"10.1371\/journal.pone.0011747","volume":"5","author":"MC Nunes","year":"2010","unstructured":"Nunes, M. C., Okada, M., Scheidig-Benatar, C., Cooke, B. M. & Scherf, A. Plasmodium falciparum FIKK kinase members target distinct components of the erythrocyte membrane. PLoS ONE 5, e11747 (2010).","journal-title":"PLoS ONE"},{"key":"2017_CR21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.molbiopara.2013.08.003","volume":"191","author":"GS Brandt","year":"2013","unstructured":"Brandt, G. S. & Bailey, S. Dematin, a human erythrocyte cytoskeletal protein, is a substrate for a recombinant FIKK kinase from Plasmodium falciparum. Mol. Biochem. Parasitol. 191, 20\u201323 (2013).","journal-title":"Mol. Biochem. Parasitol."},{"key":"2017_CR22","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.molbiopara.2015.06.002","volume":"201","author":"KT Osman","year":"2015","unstructured":"Osman, K. T. et al. Biochemical characterization of FIKK8\u2014a unique protein kinase from the malaria parasite Plasmodium falciparum and other apicomplexans. Mol. Biochem. Parasitol. 201, 85\u201389 (2015).","journal-title":"Mol. Biochem. Parasitol."},{"key":"2017_CR23","doi-asserted-by":"crossref","DOI":"10.1038\/srep39285","volume":"6","author":"DK Jaijyan","year":"2016","unstructured":"Jaijyan, D. K., Verma, P. K. & Singh, A. P. A novel FIKK kinase regulates the development of mosquito and liver stages of the malaria. Sci. Rep. 6, 39285 (2016).","journal-title":"Sci. Rep."},{"key":"2017_CR24","doi-asserted-by":"crossref","first-page":"6605","DOI":"10.1021\/acsomega.7b00997","volume":"2","author":"BC Lin","year":"2017","unstructured":"Lin, B. C. et al. FIKK kinase, a Ser\/Thr kinase important to malaria parasites, is inhibited by tyrosine kinase inhibitors. ACS Omega 2, 6605\u20136612 (2017).","journal-title":"ACS Omega"},{"key":"2017_CR25","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.bioorg.2017.09.011","volume":"75","author":"BC Lin","year":"2017","unstructured":"Lin, B. C. et al. The anthraquinone emodin inhibits the non-exported FIKK kinase from Plasmodium falciparum. Bioorg. Chem. 75, 217\u2013223 (2017).","journal-title":"Bioorg. Chem."},{"key":"2017_CR26","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1111\/cbdd.13821","volume":"97","author":"AK D","year":"2021","unstructured":"D, A. K., Shrivastava, D., Sahasrabuddhe, A. A., Habib, S. & Trivedi, V. Plasmodium falciparum FIKK9.1 is a monomeric serine-threonine protein kinase with features to exploit as a drug target. Chem. Biol. Drug Des. 97, 962\u2013977 (2021).","journal-title":"Chem. Biol. Drug Des."},{"key":"2017_CR27","doi-asserted-by":"crossref","first-page":"e139","DOI":"10.1371\/journal.pbio.0060139","volume":"6","author":"L McRobert","year":"2008","unstructured":"McRobert, L. et al. Gametogenesis in malaria parasites is mediated by the cGMP-dependent protein kinase. PLoS Biol. 6, e139 (2008).","journal-title":"PLoS Biol."},{"key":"2017_CR28","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1111\/bjh.16219","volume":"188","author":"G Siddiqui","year":"2020","unstructured":"Siddiqui, G., Proellochs, N. I. & Cooke, B. M. Identification of essential exported Plasmodium falciparum protein kinases in malaria-infected red blood cells. Br. J. Haematol. 188, 774\u2013783 (2020).","journal-title":"Br. J. Haematol."},{"key":"2017_CR29","unstructured":"MalariaGen et al. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples. Wellcome Open Res. 6, 42 (2021)."},{"key":"2017_CR30","doi-asserted-by":"crossref","DOI":"10.1128\/mbio.01768-23","volume":"14","author":"E Coonahan","year":"2023","unstructured":"Coonahan, E. et al. Whole-genome surveillance identifies markers of Plasmodium falciparum drug resistance and novel genomic regions under selection in Mozambique. mBio 14, e0176823 (2023).","journal-title":"mBio"},{"key":"2017_CR31","doi-asserted-by":"publisher","unstructured":"Howick, V. M. et al. The Malaria Cell Atlas: single parasite transcriptomes across the complete Plasmodium life cycle. Science https:\/\/doi.org\/10.1126\/science.aaw2619 (2019).","DOI":"10.1126\/science.aaw2619"},{"key":"2017_CR32","doi-asserted-by":"publisher","unstructured":"Davies, H., Belda, H., Broncel, M., Dalimot, J. & Treeck, M. PerTurboID, A targeted in situ method reveals the impact of kinase deletion on its local protein environment in the cytoadhesion complex of malaria causing parasites. eLife https:\/\/doi.org\/10.7554\/eLife.86367 (2023).","DOI":"10.7554\/eLife.86367"},{"key":"2017_CR33","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nbt.4201","volume":"36","author":"TC Branon","year":"2018","unstructured":"Branon, T. C. et al. Efficient proximity labeling in living cells and organisms with TurboID. Nat. Biotechnol. 36, 880\u2013887 (2018).","journal-title":"Nat. Biotechnol."},{"key":"2017_CR34","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1073\/pnas.0609836104","volume":"104","author":"J Villen","year":"2007","unstructured":"Villen, J., Beausoleil, S. A., Gerber, S. A. & Gygi, S. P. Large-scale phosphorylation analysis of mouse liver. Proc. Natl Acad. Sci. USA 104, 1488\u20131493 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2017_CR35","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.chom.2011.09.004","volume":"10","author":"M Treeck","year":"2011","unstructured":"Treeck, M., Sanders, J. L., Elias, J. E. & Boothroyd, J. C. The phosphoproteomes of Plasmodium falciparum and Toxoplasma gondii reveal unusual adaptations within and beyond the parasites\u2019 boundaries. Cell Host Microbe 10, 410\u2013419 (2011).","journal-title":"Cell Host Microbe"},{"key":"2017_CR36","doi-asserted-by":"crossref","DOI":"10.1186\/s12864-022-08457-0","volume":"23","author":"J Adderley","year":"2022","unstructured":"Adderley, J. & Doerig, C. Comparative analysis of the kinomes of Plasmodium falciparum, Plasmodium vivax and their host Homo sapiens. BMC Genomics 23, 237 (2022).","journal-title":"BMC Genomics"},{"key":"2017_CR37","doi-asserted-by":"crossref","first-page":"8802","DOI":"10.1074\/jbc.M311886200","volume":"279","author":"M Rodriguez","year":"2004","unstructured":"Rodriguez, M., Li, S. S., Harper, J. W. & Songyang, Z. An oriented peptide array library (OPAL) strategy to study protein\u2013protein interactions. J. Biol. Chem. 279, 8802\u20138807 (2004).","journal-title":"J. Biol. Chem."},{"key":"2017_CR38","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.micinf.2012.04.007","volume":"14","author":"D Miranda-Saavedra","year":"2012","unstructured":"Miranda-Saavedra, D., Gabaldon, T., Barton, G. J., Langsley, G. & Doerig, C. The kinomes of apicomplexan parasites. Microbes Infect. 14, 796\u2013810 (2012).","journal-title":"Microbes Infect."},{"key":"2017_CR39","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.cbpa.2017.02.020","volume":"38","author":"R Obexer","year":"2017","unstructured":"Obexer, R., Walport, L. J. & Suga, H. Exploring sequence space: harnessing chemical and biological diversity towards new peptide leads. Curr. Opin. Chem. Biol. 38, 52\u201361 (2017).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"2017_CR40","doi-asserted-by":"publisher","unstructured":"Suga, H. Max-Bergmann award lecture: a RaPID way to discover bioactive nonstandard peptides assisted by the flexizyme and FIT systems. J. Pept. Sci. https:\/\/doi.org\/10.1002\/psc.3055 (2018).","DOI":"10.1002\/psc.3055"},{"key":"2017_CR41","doi-asserted-by":"crossref","first-page":"10360","DOI":"10.1021\/acs.chemrev.8b00430","volume":"119","author":"Y Huang","year":"2019","unstructured":"Huang, Y., Wiedmann, M. M. & Suga, H. RNA display methods for the discovery of bioactive macrocycles. Chem. Rev. 119, 10360\u201310391 (2019).","journal-title":"Chem. Rev."},{"key":"2017_CR42","volume":"10","author":"R Chowdhury","year":"2020","unstructured":"Chowdhury, R. et al. Use of cyclic peptides to induce crystallization: case study with prolyl hydroxylase domain 2. Sci. Rep. 10, 21964 (2020).","journal-title":"Sci. Rep."},{"key":"2017_CR43","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1126\/science.1075762","volume":"298","author":"G Manning","year":"2002","unstructured":"Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912\u20131934 (2002).","journal-title":"Science"},{"key":"2017_CR44","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2011-12-7-r66","volume":"12","author":"G Manning","year":"2011","unstructured":"Manning, G. et al. The minimal kinome of Giardia lamblia illuminates early kinase evolution and unique parasite biology. Genome Biol. 12, R66 (2011).","journal-title":"Genome Biol."},{"key":"2017_CR45","doi-asserted-by":"crossref","first-page":"e3000341","DOI":"10.1371\/journal.pbio.3000341","volume":"17","author":"D Bradley","year":"2019","unstructured":"Bradley, D. & Beltrao, P. Evolution of protein kinase substrate recognition at the active site. PLoS Biol. 17, e3000341 (2019).","journal-title":"PLoS Biol."},{"key":"2017_CR46","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1038\/s41586-022-05575-3","volume":"613","author":"JL Johnson","year":"2023","unstructured":"Johnson, J. L. et al. An atlas of substrate specificities for the human serine\/threonine kinome. Nature 613, 759\u2013766 (2023).","journal-title":"Nature"},{"key":"2017_CR47","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1126\/science.1862343","volume":"253","author":"DR Knighton","year":"1991","unstructured":"Knighton, D. R. et al. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science 253, 414\u2013420 (1991).","journal-title":"Science"},{"key":"2017_CR48","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1073\/pnas.0134224100","volume":"100","author":"RI Brinkworth","year":"2003","unstructured":"Brinkworth, R. I., Breinl, R. A. & Kobe, B. Structural basis and prediction of substrate specificity in protein serine\/threonine kinases. Proc. Natl Acad. Sci. USA 100, 74\u201379 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2017_CR49","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrm2203","volume":"8","author":"JA Ubersax","year":"2007","unstructured":"Ubersax, J. A. & Ferrell, J. E. Jr. Mechanisms of specificity in protein phosphorylation. Nat. Rev. Mol. Cell Biol. 8, 530\u2013541 (2007).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2017_CR50","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.tibs.2018.02.009","volume":"43","author":"CJ Miller","year":"2018","unstructured":"Miller, C. J. & Turk, B. E. Homing in: mechanisms of substrate targeting by protein kinases. Trends Biochem. Sci. 43, 380\u2013394 (2018).","journal-title":"Trends Biochem. Sci."},{"key":"2017_CR51","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2020.108602","volume":"34","author":"D Bradley","year":"2021","unstructured":"Bradley, D. et al. Sequence and structure-based analysis of specificity determinants in eukaryotic protein kinases. Cell Rep. 34, 108602 (2021).","journal-title":"Cell Rep."},{"key":"2017_CR52","volume":"12","author":"HB Guo","year":"2022","unstructured":"Guo, H. B. et al. AlphaFold2 models indicate that protein sequence determines both structure and dynamics. Sci. Rep. 12, 10696 (2022).","journal-title":"Sci. Rep."},{"key":"2017_CR53","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/prot.26471","volume":"91","author":"P Ma","year":"2023","unstructured":"Ma, P., Li, D. W. & Bruschweiler, R. Predicting protein flexibility with AlphaFold. Proteins 91, 847\u2013855 (2023).","journal-title":"Proteins"},{"key":"2017_CR54","volume":"9","author":"V Modi","year":"2019","unstructured":"Modi, V. & Dunbrack, R. L. Jr. A structurally-validated multiple sequence alignment of 497 human protein kinase domains. Sci. Rep. 9, 19790 (2019).","journal-title":"Sci. Rep."},{"key":"2017_CR55","doi-asserted-by":"crossref","first-page":"14640","DOI":"10.1021\/jacs.5b07090","volume":"137","author":"A Lange","year":"2015","unstructured":"Lange, A. et al. Targeting the gatekeeper MET146 of C-Jun N-terminal kinase 3 induces a bivalent halogen\/chalcogen bond. J. Am. Chem. Soc. 137, 14640\u201314652 (2015).","journal-title":"J. Am. Chem. Soc."},{"key":"2017_CR56","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/j.1432-1033.1995.317_c.x","volume":"234","author":"F Meggio","year":"1995","unstructured":"Meggio, F. et al. Different susceptibility of protein kinases to staurosporine inhibition. Kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur. J. Biochem. 234, 317\u2013322 (1995).","journal-title":"Eur. J. Biochem."},{"key":"2017_CR57","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nbt1358","volume":"26","author":"MW Karaman","year":"2008","unstructured":"Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26, 127\u2013132 (2008).","journal-title":"Nat. Biotechnol."},{"key":"2017_CR58","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1747-0285.2009.00832.x","volume":"74","author":"D Tanramluk","year":"2009","unstructured":"Tanramluk, D., Schreyer, A., Pitt, W. R. & Blundell, T. L. On the origins of enzyme inhibitor selectivity and promiscuity: a case study of protein kinase binding to staurosporine. Chem. Biol. Drug Des. 74, 16\u201324 (2009).","journal-title":"Chem. Biol. Drug Des."},{"key":"2017_CR59","doi-asserted-by":"crossref","first-page":"340","DOI":"10.2174\/1568026613666131127160819","volume":"14","author":"DH Drewry","year":"2014","unstructured":"Drewry, D. H., Willson, T. M. & Zuercher, W. J. Seeding collaborations to advance kinase science with the GSK Published Kinase Inhibitor Set (PKIS). Curr. Top. Med. Chem. 14, 340\u2013342 (2014).","journal-title":"Curr. Top. Med. Chem."},{"key":"2017_CR60","doi-asserted-by":"crossref","first-page":"e0181585","DOI":"10.1371\/journal.pone.0181585","volume":"12","author":"DH Drewry","year":"2017","unstructured":"Drewry, D. H. et al. Progress towards a public chemogenomic set for protein kinases and a call for contributions. PLoS ONE 12, e0181585 (2017).","journal-title":"PLoS ONE"},{"key":"2017_CR61","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41378-019-0097-7","volume":"5","author":"Z Xu","year":"2019","unstructured":"Xu, Z., Dou, W., Wang, C. & Sun, Y. Stiffness and ATP recovery of stored red blood cells in serum. Microsyst. Nanoeng. 5, 51 (2019).","journal-title":"Microsyst. Nanoeng."},{"key":"2017_CR62","doi-asserted-by":"crossref","unstructured":"Lew, V. L. & Ferreira, H. G. in Current Topics in Membranes and Transport Vol. 10 (eds Bronner, F. & Kleinzeller, A.) 217\u2013277 (Academic, 1978).","DOI":"10.1016\/S0070-2161(08)60836-9"},{"key":"2017_CR63","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1182\/blood-2006-08-043364","volume":"109","author":"AG Maier","year":"2007","unstructured":"Maier, A. G. et al. Skeleton-binding protein 1 functions at the parasitophorous vacuole membrane to traffic PfEMP1 to the Plasmodium falciparum-infected erythrocyte surface. Blood 109, 1289\u20131297 (2007).","journal-title":"Blood"},{"key":"2017_CR64","doi-asserted-by":"publisher","unstructured":"Hamilton, W. L. et al. A fourth locus in the Plasmodium falciparum genome associated with sickle haemoglobin. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2023.09.14.557461 (2023).","DOI":"10.1101\/2023.09.14.557461"},{"key":"2017_CR65","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1002\/pmic.201000269","volume":"10","author":"A Pantaleo","year":"2010","unstructured":"Pantaleo, A. et al. Analysis of changes in tyrosine and serine phosphorylation of red cell membrane proteins induced by P. falciparum growth. Proteomics 10, 3469\u20133479 (2010).","journal-title":"Proteomics"},{"key":"2017_CR66","doi-asserted-by":"crossref","first-page":"e0164895","DOI":"10.1371\/journal.pone.0164895","volume":"11","author":"KR Kesely","year":"2016","unstructured":"Kesely, K. R., Pantaleo, A., Turrini, F. M., Olupot-Olupot, P. & Low, P. S. Inhibition of an erythrocyte tyrosine kinase with imatinib prevents Plasmodium falciparum egress and terminates parasitemia. PLoS ONE 11, e0164895 (2016).","journal-title":"PLoS ONE"},{"key":"2017_CR67","doi-asserted-by":"crossref","first-page":"5496","DOI":"10.1182\/bloodadvances.2023010844","volume":"7","author":"TP Feldman","year":"2023","unstructured":"Feldman, T. P., Ryan, Y. & Egan, E. S. Plasmodium falciparum infection of human erythroblasts induces transcriptional changes associated with dyserythropoiesis. Blood Adv. 7, 5496\u20135509 (2023).","journal-title":"Blood Adv."},{"key":"2017_CR68","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/nrmicro1529","volume":"4","author":"M Prudencio","year":"2006","unstructured":"Prudencio, M., Rodriguez, A. & Mota, M. M. The silent path to thousands of merozoites: the Plasmodium liver stage. Nat. Rev. Microbiol. 4, 849\u2013856 (2006).","journal-title":"Nat. Rev. Microbiol."},{"key":"2017_CR69","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/nature05395","volume":"445","author":"JP Saeij","year":"2007","unstructured":"Saeij, J. P. et al. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445, 324\u2013327 (2007).","journal-title":"Nature"},{"key":"2017_CR70","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-024-50812-0","volume":"15","author":"J Gizzio","year":"2024","unstructured":"Gizzio, J., Thakur, A., Haldane, A., Post, C. B. & Levy, R. M. Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser\/Thr kinases. Nat. Commun. 15, 6545 (2024).","journal-title":"Nat. Commun."},{"key":"2017_CR71","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1038\/s41586-024-07407-y","volume":"629","author":"TM Yaron-Barir","year":"2024","unstructured":"Yaron-Barir, T. M. et al. The intrinsic substrate specificity of the human tyrosine kinome. Nature 629, 1174\u20131181 (2024).","journal-title":"Nature"},{"key":"2017_CR72","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","volume":"23","author":"B Blasco","year":"2017","unstructured":"Blasco, B., Leroy, D. & Fidock, D. A. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat. Med. 23, 917\u2013928 (2017).","journal-title":"Nat. Med."},{"key":"2017_CR73","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1126\/science.1260403","volume":"347","author":"S Mok","year":"2015","unstructured":"Mok, S. et al. Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science 347, 431\u2013435 (2015).","journal-title":"Science"},{"key":"2017_CR74","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1093\/nar\/gkv1214","volume":"44","author":"PR Kensche","year":"2016","unstructured":"Kensche, P. R. et al. The nucleosome landscape of Plasmodium falciparum reveals chromatin architecture and dynamics of regulatory sequences. Nucleic Acids Res. 44, 2110\u20132124 (2016).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR75","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","volume":"193","author":"W Trager","year":"1976","unstructured":"Trager, W. & Jensen, J. B. Human malaria parasites in continuous culture. Science 193, 673\u2013675 (1976).","journal-title":"Science"},{"key":"2017_CR76","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1073\/pnas.1216457110","volume":"110","author":"RW Moon","year":"2013","unstructured":"Moon, R. W. et al. Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes. Proc. Natl Acad. Sci. USA 110, 531\u2013536 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2017_CR77","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.molbiopara.2007.04.008","volume":"154","author":"QL Fivelman","year":"2007","unstructured":"Fivelman, Q. L. et al. Improved synchronous production of Plasmodium falciparum gametocytes in vitro. Mol. Biochem. Parasitol. 154, 119\u2013123 (2007).","journal-title":"Mol. Biochem. Parasitol."},{"key":"2017_CR78","volume":"6","author":"ML Jones","year":"2016","unstructured":"Jones, M. L. et al. A versatile strategy for rapid conditional genome engineering using loxP sites in a small synthetic intron in Plasmodium falciparum. Sci. Rep. 6, 21800 (2016).","journal-title":"Sci. Rep."},{"key":"2017_CR79","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.molbiopara.2006.01.009","volume":"147","author":"ML Jones","year":"2006","unstructured":"Jones, M. L., Kitson, E. L. & Rayner, J. C. Plasmodium falciparum erythrocyte invasion: a conserved myosin associated complex. Mol. Biochemical Parasitol. 147, 74\u201384 (2006).","journal-title":"Mol. Biochemical Parasitol."},{"key":"2017_CR80","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0166-6851(83)90025-7","volume":"7","author":"R Hall","year":"1983","unstructured":"Hall, R. et al. Antigens of the erythrocytes stages of the human malaria parasite Plasmodium falciparum detected by monoclonal antibodies. Mol. Biochem. Parasitol. 7, 247\u2013265 (1983).","journal-title":"Mol. Biochem. Parasitol."},{"key":"2017_CR81","volume":"1","author":"D Peng","year":"2015","unstructured":"Peng, D. & Tarleton, R. EuPaGDT: a web tool tailored to design CRISPR guide RNAs for eukaryotic pathogens. Microb. Genom. 1, e000033 (2015).","journal-title":"Microb. Genom."},{"key":"2017_CR82","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-03984-3","volume":"7","author":"E Knuepfer","year":"2017","unstructured":"Knuepfer, E., Napiorkowska, M., van Ooij, C. & Holder, A. A. Generating conditional gene knockouts in Plasmodium\u2014a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR\u2013Cas9. Sci. Rep. 7, 3881 (2017).","journal-title":"Sci. Rep."},{"key":"2017_CR83","doi-asserted-by":"publisher","unstructured":"Tiburcio, M. et al. A novel tool for the generation of conditional knockouts to study gene function across the Plasmodium falciparum life cycle. mBio https:\/\/doi.org\/10.1128\/mBio.01170-19 (2019).","DOI":"10.1128\/mBio.01170-19"},{"key":"2017_CR84","doi-asserted-by":"crossref","first-page":"D523","DOI":"10.1093\/nar\/gkac1052","volume":"51","author":"The UniProt Consortium.","year":"2023","unstructured":"The UniProt Consortium. UniProt: the universal protein knowledgebase in 2023. Nucleic Acids Res. 51, D523\u2013D531 (2023).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR85","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/nar\/gki198","volume":"33","author":"K Katoh","year":"2005","unstructured":"Katoh, K., Kuma, K., Toh, H. & Miyata, T. MAFFT version 5: improvement in accuracy of multiple sequence alignment. Nucleic Acids Res. 33, 511\u2013518 (2005).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR86","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1093\/bioinformatics\/btp348","volume":"25","author":"S Capella-Gutierrez","year":"2009","unstructured":"Capella-Gutierrez, S., Silla-Martinez, J. M. & Gabaldon, T. trimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses. Bioinformatics 25, 1972\u20131973 (2009).","journal-title":"Bioinformatics"},{"key":"2017_CR87","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.1093\/molbev\/msaa015","volume":"37","author":"BQ Minh","year":"2020","unstructured":"Minh, B. Q. et al. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol. Biol. Evol. 37, 1530\u20131534 (2020).","journal-title":"Mol. Biol. Evol."},{"key":"2017_CR88","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nmeth.4285","volume":"14","author":"S Kalyaanamoorthy","year":"2017","unstructured":"Kalyaanamoorthy, S., Minh, B. Q., Wong, T. K. F., von Haeseler, A. & Jermiin, L. S. ModelFinder: fast model selection for accurate phylogenetic estimates. Nat. Methods 14, 587\u2013589 (2017).","journal-title":"Nat. Methods"},{"key":"2017_CR89","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2307\/2408678","volume":"39","author":"J Felsenstein","year":"1985","unstructured":"Felsenstein, J. Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39, 783\u2013791 (1985).","journal-title":"Evolution"},{"key":"2017_CR90","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1093\/molbev\/msy194","volume":"35","author":"G Yu","year":"2018","unstructured":"Yu, G., Lam, T. T., Zhu, H. & Guan, Y. Two methods for mapping and visualizing associated data on phylogeny using Ggtree. Mol. Biol. Evol. 35, 3041\u20133043 (2018).","journal-title":"Mol. Biol. Evol."},{"key":"2017_CR91","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/molbev\/msm088","volume":"24","author":"Z Yang","year":"2007","unstructured":"Yang, Z. PAML 4: phylogenetic analysis by maximum likelihood. Mol. Biol. Evol. 24, 1586\u20131591 (2007).","journal-title":"Mol. Biol. Evol."},{"key":"2017_CR92","doi-asserted-by":"publisher","unstructured":"Alvarez-Carretero, S., Kapli, P. & Yang, Z. Beginner\u2019s guide on the use of PAML to detect positive selection. Mol. Biol. Evol. https:\/\/doi.org\/10.1093\/molbev\/msad041 (2023).","DOI":"10.1093\/molbev\/msad041"},{"key":"2017_CR93","doi-asserted-by":"crossref","first-page":"W7","DOI":"10.1093\/nar\/gkq291","volume":"38","author":"F Abascal","year":"2010","unstructured":"Abascal, F., Zardoya, R. & Telford, M. J. TranslatorX: multiple alignment of nucleotide sequences guided by amino acid translations. Nucleic Acids Res. 38, W7\u2013W13 (2010).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR94","doi-asserted-by":"crossref","first-page":"e1005618","DOI":"10.1371\/journal.ppat.1005618","volume":"12","author":"P Mesen-Ramirez","year":"2016","unstructured":"Mesen-Ramirez, P. et al. Stable translocation intermediates jam global protein export in Plasmodium falciparum parasites and link the PTEX component EXP2 with translocation activity. PLoS Pathog. 12, e1005618 (2016).","journal-title":"PLoS Pathog."},{"key":"2017_CR95","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1021\/acs.jproteome.7b00775","volume":"17","author":"DI Kim","year":"2018","unstructured":"Kim, D. I. et al. BioSITe: a method for direct detection and quantitation of site-specific biotinylation. J. Proteome Res. 17, 759\u2013769 (2018).","journal-title":"J. Proteome Res."},{"key":"2017_CR96","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/nbt.1511","volume":"26","author":"J Cox","year":"2008","unstructured":"Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367\u20131372 (2008).","journal-title":"Nat. Biotechnol."},{"key":"2017_CR97","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1021\/pr101065j","volume":"10","author":"J Cox","year":"2011","unstructured":"Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794\u20131805 (2011).","journal-title":"J. Proteome Res."},{"key":"2017_CR98","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731\u2013740 (2016).","journal-title":"Nat. Methods"},{"key":"2017_CR99","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498\u20132504 (2003).","journal-title":"Genome Res."},{"key":"2017_CR100","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1093\/nar\/gkg585","volume":"31","author":"AE Kel","year":"2003","unstructured":"Kel, A. E. et al. MATCH: a tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 31, 3576\u20133579 (2003).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR101","unstructured":"Codon optimization tool. IDT https:\/\/eu.idtdna.com\/CodonOpt (2025)."},{"key":"2017_CR102","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/nprot.2006.57","volume":"1","author":"BE Turk","year":"2006","unstructured":"Turk, B. E., Hutti, J. E. & Cantley, L. C. Determining protein kinase substrate specificity by parallel solution-phase assay of large numbers of peptide substrates. Nat. Protoc. 1, 375\u2013379 (2006).","journal-title":"Nat. Protoc."},{"key":"2017_CR103","first-page":"ra12","volume":"3","author":"J Mok","year":"2010","unstructured":"Mok, J. et al. Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Sci. Signal. 3, ra12 (2010).","journal-title":"Sci. Signal."},{"key":"2017_CR104","doi-asserted-by":"crossref","first-page":"e2006540","DOI":"10.1371\/journal.pbio.2006540","volume":"17","author":"CJ Miller","year":"2019","unstructured":"Miller, C. J. et al. Comprehensive profiling of the STE20 kinase family defines features essential for selective substrate targeting and signaling output. PLoS Biol. 17, e2006540 (2019).","journal-title":"PLoS Biol."},{"key":"2017_CR105","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1093\/bioinformatics\/btx469","volume":"33","author":"O Wagih","year":"2017","unstructured":"Wagih, O. ggseqlogo: a versatile R package for drawing sequence logos. Bioinformatics 33, 3645\u20133647 (2017).","journal-title":"Bioinformatics"},{"key":"2017_CR106","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/bioinformatics\/btl461","volume":"22","author":"BJ Grant","year":"2006","unstructured":"Grant, B. J., Rodrigues, A. P. C., ElSawy, K. M., McCammon, J. A. & Caves, L. S. D. Bio3d: an R package for the comparative analysis of protein structures. Bioinformatics 22, 2695\u20132696 (2006).","journal-title":"Bioinformatics"},{"key":"2017_CR107","doi-asserted-by":"crossref","first-page":"5469","DOI":"10.1038\/s41467-021-25480-z","volume":"12","author":"J Huo","year":"2021","unstructured":"Huo, J. et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat. Commun. 12, 5469 (2021).","journal-title":"Nat. Commun."},{"key":"2017_CR108","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nprot.2014.039","volume":"9","author":"E Pardon","year":"2014","unstructured":"Pardon, E. et al. A general protocol for the generation of Nanobodies for structural biology. Nat. Protoc. 9, 674\u2013693 (2014).","journal-title":"Nat. Protoc."},{"key":"2017_CR109","doi-asserted-by":"publisher","unstructured":"Moutel, S. et al. NaLi-H1: A universal synthetic library of humanized nanobodies providing highly functional antibodies and intrabodies. eLife https:\/\/doi.org\/10.7554\/eLife.16228 (2016).","DOI":"10.7554\/eLife.16228"},{"key":"2017_CR110","doi-asserted-by":"crossref","DOI":"10.3389\/fmolb.2021.729513","volume":"8","author":"RV Honorato","year":"2021","unstructured":"Honorato, R. V. et al. Structural biology in the clouds: the WeNMR-EOSC ecosystem. Front. Mol. Biosci. 8, 729513 (2021).","journal-title":"Front. Mol. Biosci."},{"key":"2017_CR111","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583\u2013589 (2021).","journal-title":"Nature"},{"key":"2017_CR112","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","volume":"50","author":"M Varadi","year":"2021","unstructured":"Varadi, M. et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439\u2013D444 (2021).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR113","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1021\/ja026939x","volume":"125","author":"C Dominguez","year":"2003","unstructured":"Dominguez, C., Boelens, R. & Bonvin, A. M. HADDOCK: a protein\u2013protein docking approach based on biochemical or biophysical information. J. Am. Chem. Soc. 125, 1731\u20131737 (2003).","journal-title":"J. Am. Chem. Soc."},{"key":"2017_CR114","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkab1038","volume":"50","author":"Y Perez-Riverol","year":"2022","unstructured":"Perez-Riverol, Y. et al. The PRIDE database resources in 2022: a hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543\u2013D552 (2022).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR115","unstructured":"The PyMOL Molecular Graphics System v2.5.4 (Schr\u00f6dinger, 2022)."},{"key":"2017_CR116","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0097-8485(99)00012-1","volume":"23","author":"J Heringa","year":"1999","unstructured":"Heringa, J. Two strategies for sequence comparison: profile-preprocessed and secondary structure-induced multiple alignment. Comput. Chem. 23, 341\u2013364 (1999).","journal-title":"Comput. Chem."},{"key":"2017_CR117","doi-asserted-by":"crossref","first-page":"W276","DOI":"10.1093\/nar\/gkac240","volume":"50","author":"F Madeira","year":"2022","unstructured":"Madeira, F. et al. Search and sequence analysis tools services from EMBL-EBI in 2022. Nucleic Acids Res. 50, W276\u2013W279 (2022).","journal-title":"Nucleic Acids Res."},{"key":"2017_CR118","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/bioinformatics\/btp033","volume":"25","author":"AM Waterhouse","year":"2009","unstructured":"Waterhouse, A. M., Procter, J. B., Martin, D. M., Clamp, M. & Barton, G. J. Jalview version 2\u2014a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189\u20131191 (2009).","journal-title":"Bioinformatics"},{"key":"2017_CR119","first-page":"745","volume":"9","author":"CD Livingstone","year":"1993","unstructured":"Livingstone, C. D. & Barton, G. J. Protein sequence alignments: a strategy for the hierarchical analysis of residue conservation. Comput. Appl. Biosci. 9, 745\u2013756 (1993).","journal-title":"Comput. Appl. Biosci."},{"key":"2017_CR120","doi-asserted-by":"publisher","unstructured":"Reinhardt, R. & Leonard, T. A. A critical evaluation of protein kinase regulation by activation loop autophosphorylation. eLife https:\/\/doi.org\/10.7554\/eLife.88210 (2023).","DOI":"10.7554\/eLife.88210"},{"key":"2017_CR121","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.chembiol.2013.06.001","volume":"20","author":"DK Treiber","year":"2013","unstructured":"Treiber, D. K. & Shah, N. P. Ins and outs of kinase DFG motifs. Chem. Biol. 20, 745\u2013746 (2013).","journal-title":"Chem. Biol."},{"key":"2017_CR122","doi-asserted-by":"crossref","first-page":"W320","DOI":"10.1093\/nar\/gku316","volume":"42","author":"X Robert","year":"2014","unstructured":"Robert, X. & Gouet, P. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 42, W320\u2013W324 (2014).","journal-title":"Nucleic Acids Res."}],"container-title":["Nature Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02017-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02017-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02017-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T22:02:52Z","timestamp":1749074572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41564-025-02017-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,19]]},"references-count":122,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["2017"],"URL":"https:\/\/doi.org\/10.1038\/s41564-025-02017-4","relation":{},"ISSN":["2058-5276"],"issn-type":[{"value":"2058-5276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,19]]},"assertion":[{"value":"19 March 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}