{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:36:40Z","timestamp":1791992200960,"version":"4.4.0"},"reference-count":78,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI43957"],"award-info":[{"award-number":["AI43957"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Bruton\u2019s tyrosine kinase (BTK) is targeted in the treatment of B-cell disorders including leukemias and lymphomas. Currently approved BTK inhibitors, including Ibrutinib, a first-in-class covalent inhibitor of BTK, bind directly to the kinase active site. While effective at blocking the catalytic activity of BTK, consequences of drug binding on the global conformation of full-length BTK are unknown. Here, we uncover a range of conformational effects in full-length BTK induced by a panel of active site inhibitors, including large-scale shifts in the conformational equilibria of the regulatory domains. Additionally, we find that a remote Ibrutinib resistance mutation, T316A in the BTK SH2 domain, drives spurious BTK activity by destabilizing the compact autoinhibitory conformation of full-length BTK, shifting the conformational ensemble away from the autoinhibited form. Future development of BTK inhibitors will need to consider long-range allosteric consequences of inhibitor binding, including the emerging application of these BTK inhibitors in treating COVID-19.<\/jats:p>","DOI":"10.7554\/elife.60470","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T08:21:19Z","timestamp":1606119679000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.60470","source":"Crossref","is-referenced-by-count":46,"title":["Differential impact of BTK active site inhibitors on the conformational state of full-length BTK"],"prefix":"10.7554","volume":"9","author":[{"given":"Raji E","family":"Joseph","sequence":"first","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Amatya","sequence":"additional","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Bruce","family":"Fulton","sequence":"additional","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6918-9476","authenticated-orcid":true,"given":"John R","family":"Engen","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E","family":"Wales","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, Northeastern University, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6952-7244","authenticated-orcid":true,"given":"Amy","family":"Andreotti","sequence":"additional","affiliation":[{"name":"Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1200\/JCO.2012.42.7906","article-title":"Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed\/refractory B-cell malignancies","volume":"31","author":"Advani","year":"2013","journal-title":"Journal of Clinical Oncology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"21539","DOI":"10.1073\/pnas.1907566116","article-title":"Lipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases","volume":"116","author":"Amatya","year":"2019","journal-title":"PNAS"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1007\/s40266-017-0468-4","article-title":"Current status of Bruton's Tyrosine Kinase Inhibitor Development and Use in B-Cell Malignancies","volume":"34","author":"Aw","year":"2017","journal-title":"Drugs & Aging"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1124\/jpet.117.242909","article-title":"Acalabrutinib (ACP-196): A covalent bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile","volume":"363","author":"Barf","year":"2017","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"6243","DOI":"10.1021\/jm3003203","article-title":"Irreversible protein kinase inhibitors: balancing the benefits and risks","volume":"55","author":"Barf","year":"2012","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.drudis.2015.05.005","article-title":"Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies","volume":"20","author":"Bauer","year":"2015","journal-title":"Drug Discovery Today"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1124\/mol.116.107037","article-title":"Ability of Bruton's Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling","volume":"91","author":"Bender","year":"2017","journal-title":"Molecular Pharmacology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1146\/annurev.immunol.22.012703.104743","article-title":"Tec family kinases in T lymphocyte development and function","volume":"23","author":"Berg","year":"2005","journal-title":"Annual Review of Immunology"},{"key":"bib9","first-page":"223","article-title":"Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions","volume":"17","author":"Bond","year":"2019","journal-title":"Clinical Advances in Hematology & Oncology : H&O"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"e295","DOI":"10.3324\/haematol.2015.140806","article-title":"Phase I study of single-agent CC-292, a highly selective Bruton's tyrosine kinase inhibitor, in relapsed\/refractory chronic lymphocytic leukemia","volume":"101","author":"Brown","year":"2016","journal-title":"Haematologica"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1038\/leu.2014.263","article-title":"Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors","volume":"29","author":"Cheng","year":"2015","journal-title":"Leukemia"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1021\/acs.jmedchem.7b01712","article-title":"Discovery of GDC-0853: a potent, selective, and noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development","volume":"61","author":"Crawford","year":"2018","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"957","DOI":"10.2217\/fon.14.51","article-title":"Ibrutinib: a first in class covalent inhibitor of Bruton's tyrosine kinase","volume":"10","author":"Davids","year":"2014","journal-title":"Future Oncology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1021\/acs.biochem.6b01182","article-title":"An autoinhibitory role for the pleckstrin homology domain of Interleukin-2-Inducible tyrosine kinase and its interplay with canonical phospholipid recognition","volume":"56","author":"Devkota","year":"2017","journal-title":"Biochemistry"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nchembio.481","article-title":"Specific btk inhibition suppresses B cell- and myeloid cell-mediated arthritis","volume":"7","author":"Di Paolo","year":"2011","journal-title":"Nature Chemical Biology"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1111\/j.1742-4658.2011.08073.x","article-title":"Tec family kinases: regulation of Fc\u03b5RI-mediated mast-cell activation","volume":"278","author":"Ellmeier","year":"2011","journal-title":"FEBS Journal"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"2675","DOI":"10.1111\/bph.13096","article-title":"Ten things you should know about protein kinases: iuphar review 14","volume":"172","author":"Fabbro","year":"2015","journal-title":"British Journal of Pharmacology"},{"key":"bib18","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.0c00429","article-title":"How ATP-Competitive inhibitors allosterically modulate tyrosine kinases that contain a Src-like regulatory architecture","volume-title":"ChemRxiv","author":"Fang","year":"2020"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1080\/13543776.2019.1594777","article-title":"Bruton's tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)","volume":"29","author":"Feng","year":"2019","journal-title":"Expert Opinion on Therapeutic Patents"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1021\/jacs.7b09974","article-title":"Slow dynamics of Tryptophan-Water networks in proteins","volume":"140","author":"Fenwick","year":"2018","journal-title":"Journal of the American Chemical Society"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1056\/NEJMc1402716","article-title":"Ibrutinib resistance in chronic lymphocytic leukemia","volume":"370","author":"Furman","year":"2014","journal-title":"New England Journal of Medicine"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/j.bpj.2020.09.019","article-title":"Synergistic allostery in Multiligand-Protein interactions","volume":"119","author":"Ghode","year":"2020","journal-title":"Biophysical Journal"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"7923","DOI":"10.1021\/acs.jmedchem.9b00687","article-title":"Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton's Tyrosine Kinase","volume":"62","author":"Guo","year":"2019","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1002\/eji.200636451","article-title":"Btk and phospholipase C gamma 2 can function independently during B cell development","volume":"37","author":"Halcomb","year":"2007","journal-title":"European Journal of Immunology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1038\/leu.2016.153","article-title":"Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant","volume":"31","author":"Hamasy","year":"2017","journal-title":"Leukemia"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1136\/annrheumdis-2013-204143","article-title":"Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants","volume":"74","author":"Hartkamp","year":"2015","journal-title":"Annals of the Rheumatic Diseases"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1007\/BF00404272","article-title":"NMR view: a computer program for the visualization and analysis of NMR data","volume":"4","author":"Johnson","year":"1994","journal-title":"Journal of Biomolecular NMR"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"5455","DOI":"10.1021\/bi602512e","article-title":"The Linker between SH2 and kinase domains positively regulates catalysis of the tec family kinases","volume":"46","author":"Joseph","year":"2007","journal-title":"Biochemistry"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1016\/j.str.2017.07.014","article-title":"Achieving a graded immune response: btk adopts a range of active\/Inactive conformations dictated by multiple interdomain contacts","volume":"25","author":"Joseph","year":"2017","journal-title":"Structure"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1182\/bloodadvances.2016003632","article-title":"Clonal evolution underlying leukemia progression and richter transformation in patients with ibrutinib-relapsed CLL","volume":"1","author":"Kadri","year":"2017","journal-title":"Blood Advances"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s12272-019-01124-1","article-title":"Development of BTK inhibitors for the treatment of B-cell malignancies","volume":"42","author":"Kim","year":"2019","journal-title":"Archives of Pharmacal Research"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"14377","DOI":"10.1073\/pnas.0807988105","article-title":"A Helix scaffold for the assembly of active protein kinases","volume":"105","author":"Kornev","year":"2008","journal-title":"PNAS"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.bbapap.2009.10.017","article-title":"Defining the conserved internal architecture of a protein kinase","volume":"1804","author":"Kornev","year":"2010","journal-title":"Biochimica Et Biophysica Acta (BBA) - Proteins and Proteomics"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1002\/pro.575","article-title":"Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures","volume":"20","author":"Kuglstatter","year":"2011","journal-title":"Protein Science"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.molimm.2010.12.007","article-title":"Regulation of BCR signaling","volume":"48","author":"Kurosaki","year":"2011","journal-title":"Molecular Immunology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1080\/17474086.2018.1435268","article-title":"Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?","volume":"11","author":"Lampson","year":"2018","journal-title":"Expert Review of Hematology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1021\/cb500371g","article-title":"Divergent modulation of Src-family kinase regulatory interactions with ATP-competitive inhibitors","volume":"9","author":"Leonard","year":"2014","journal-title":"ACS Chemical Biology"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1189\/jlb.0513307","article-title":"Bruton's tyrosine kinase--an integral protein of B cell development that also has an essential role in the innate immune system","volume":"95","author":"L\u00f3pez-Herrera","year":"2014","journal-title":"Journal of Leukocyte Biology"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"2249","DOI":"10.1158\/1078-0432.CCR-13-1610","article-title":"Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies","volume":"20","author":"Lovly","year":"2014","journal-title":"Clinical Cancer Research"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1002\/pro.321","article-title":"Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases","volume":"19","author":"Marcotte","year":"2010","journal-title":"Protein Science"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/s41592-019-0459-y","article-title":"Recommendations for performing, interpreting and reporting hydrogen deuterium exchange mass spectrometry (HDX-MS) experiments","volume":"16","author":"Masson","year":"2019","journal-title":"Nature Methods"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"5988","DOI":"10.4049\/jimmunol.171.11.5988","article-title":"Function of Bruton's tyrosine kinase during B cell development is partially independent of its catalytic activity","volume":"171","author":"Middendorp","year":"2003","journal-title":"The Journal of Immunology"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1182\/blood-2004-07-2708","article-title":"Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity","volume":"105","author":"Middendorp","year":"2005","journal-title":"Blood"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/j.1600-065X.2008.00741.x","article-title":"Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain","volume":"228","author":"Mohamed","year":"2009","journal-title":"Immunological Reviews"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1002\/hon.2695","article-title":"Ibrutinib in the treatment of chronic lymphocytic leukemia: 5\u2009years on","volume":"38","author":"Molica","year":"2020","journal-title":"Hematological Oncology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/nchembio.1938","article-title":"The ins and outs of selective kinase inhibitor development","volume":"11","author":"M\u00fcller","year":"2015","journal-title":"Nature Chemical Biology"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.3747\/co.26.4345","article-title":"Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma","volume":"26","author":"Owen","year":"2019","journal-title":"Current Oncology"},{"key":"bib48","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0779-z","article-title":"Role of Bruton's tyrosine kinase in B cells and malignancies","volume":"17","author":"Pal Singh","year":"2018","journal-title":"Molecular Cancer"},{"key":"bib49","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11121834","article-title":"Overcoming ibrutinib resistance in chronic lymphocytic leukemia","volume":"11","author":"Pu\u0142a","year":"2019","journal-title":"Cancers"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1006\/smim.1995.0028","article-title":"The btk subfamily of cytoplasmic tyrosine kinases: structure, regulation and function","volume":"7","author":"Rawlings","year":"1995","journal-title":"Seminars in Immunology"},{"key":"bib51","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abd0110","article-title":"Inhibition of Bruton tyrosine kinase in patients with severe COVID-19","volume":"5","author":"Roschewski","year":"2020","journal-title":"Science Immunology"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.phrs.2015.10.021","article-title":"Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes","volume":"103","author":"Roskoski","year":"2016","journal-title":"Pharmacological Research"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/s1074-7613(03)00297-8","article-title":"BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity","volume":"19","author":"Saito","year":"2003","journal-title":"Immunity"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"68833","DOI":"10.18632\/oncotarget.11932","article-title":"Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL","volume":"7","author":"Sharma","year":"2016","journal-title":"Oncotarget"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"3278","DOI":"10.1182\/blood-2008-10-183665","article-title":"BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib","volume":"116","author":"Sherbenou","year":"2010","journal-title":"Blood"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"E4437","DOI":"10.1073\/pnas.1314712110","article-title":"NMR reveals the allosteric opening and closing of Abelson tyrosine kinase by ATP-site and myristoyl pocket inhibitors","volume":"110","author":"Skora","year":"2013","journal-title":"PNAS"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1038\/onc.2016.343","article-title":"From identification of the BTK kinase to effective management of leukemia","volume":"36","author":"Smith","year":"2017","journal-title":"Oncogene"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1021\/jacs.7b12430","article-title":"ATP site ligands determine the assembly state of the Abelson kinase regulatory core via the activation loop conformation","volume":"140","author":"Sonti","year":"2018","journal-title":"Journal of the American Chemical Society"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1016\/j.bbapap.2015.04.007","article-title":"Integration of signaling in the kinome: architecture and regulation of the \u03b1c Helix","volume":"1854","author":"Taylor","year":"2015","journal-title":"Biochimica Et Biophysica Acta (BBA) - Proteins and Proteomics"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.tibs.2010.09.006","article-title":"Protein kinases: evolution of dynamic regulatory proteins","volume":"36","author":"Taylor","year":"2011","journal-title":"Trends in Biochemical Sciences"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02240-6","article-title":"Survey of solution dynamics in src kinase reveals allosteric cross talk between the ligand binding and regulatory sites","volume":"8","author":"Tong","year":"2017","journal-title":"Nature Communications"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1056\/NEJMoa1501548","article-title":"Ibrutinib in previously treated waldenstr\u00f6m's macroglobulinemia","volume":"372","author":"Treon","year":"2015","journal-title":"New England Journal of Medicine"},{"key":"bib63","doi-asserted-by":"publisher","DOI":"10.1038\/srep30832","article-title":"Imatinib binding to human c-Src is coupled to inter-domain allostery and suggests a novel kinase inhibition strategy","volume":"6","author":"Tsutsui","year":"2016","journal-title":"Scientific Reports"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"D447","DOI":"10.1093\/nar\/gkv1145","article-title":"2016 update of the PRIDE database and its related tools","volume":"44","author":"Vizca\u00edno","year":"2016","journal-title":"Nucleic Acids Research"},{"key":"bib65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17703-5","article-title":"A switch in nucleotide affinity governs activation of the src and tec family kinases","volume":"7","author":"von Rau\u00dfendorf","year":"2017","journal-title":"Scientific Reports"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1056\/NEJMoa1306220","article-title":"Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma","volume":"369","author":"Wang","year":"2013","journal-title":"New England Journal of Medicine"},{"key":"bib67","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.06074","article-title":"Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate","volume":"4","author":"Wang","year":"2015","journal-title":"eLife"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"5717","DOI":"10.1074\/jbc.RA119.011946","article-title":"Noncatalytic Bruton's tyrosine kinase activates PLC\u03b3 2 variants mediating ibrutinib resistance in human chronic lymphocytic leukemia cells","volume":"295","author":"Wist","year":"2020","journal-title":"Journal of Biological Chemistry"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1056\/NEJMoa1400029","article-title":"Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib","volume":"370","author":"Woyach","year":"2014","journal-title":"New England Journal of Medicine"},{"key":"bib70","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-016-0313-y","article-title":"Second-generation inhibitors of Bruton tyrosine kinase","volume":"9","author":"Wu","year":"2016","journal-title":"Journal of Hematology & Oncology"},{"key":"bib71","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc2754","article-title":"Conformational states dynamically populated by a kinase determine its function","volume":"370","author":"Xie","year":"2020","journal-title":"Science"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"675","DOI":"10.4155\/fmc.14.24","article-title":"Bruton's TK inhibitors: structural insights and evolution of clinical candidates","volume":"6","author":"Xing","year":"2014","journal-title":"Future Medicinal Chemistry"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1124\/jpet.111.187740","article-title":"RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents","volume":"341","author":"Xu","year":"2012","journal-title":"Journal of Pharmacology and Experimental Therapeutics"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.ccr.2014.06.023","article-title":"Ibrutinib treatment of CLL: the Cancer fights back","volume":"26","author":"Young","year":"2014","journal-title":"Cancer Cell"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1073\/pnas.0709662105","article-title":"The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP","volume":"105","author":"Yun","year":"2008","journal-title":"PNAS"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1111\/bjh.13427","article-title":"Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma","volume":"170","author":"Zhang","year":"2015","journal-title":"British Journal of Haematology"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.drudis.2018.01.035","article-title":"Progress with covalent small-molecule kinase inhibitors","volume":"23","author":"Zhao","year":"2018","journal-title":"Drug Discovery Today"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.3892\/or.2019.7364","article-title":"Ibrutinib in CLL\/SLL: from bench to bedside (Review)","volume":"42","author":"Zi","year":"2019","journal-title":"Oncology Reports"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/60470\/elife-60470-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/60470\/elife-60470-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/60470","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:15:21Z","timestamp":1697058921000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/60470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,23]]},"references-count":78,"alternative-id":["10.7554\/eLife.60470"],"URL":"https:\/\/doi.org\/10.7554\/elife.60470","archive":["CLOCKSS"],"relation":{"is-supplemented-by":[{"id-type":"accession","id":"PXD020029","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.60470.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.60470.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,23]]},"article-number":"e60470"}}