{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T19:25:15Z","timestamp":1794338715654,"version":"4.9.0"},"reference-count":62,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:00:00Z","timestamp":1791936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"DOI":"10.1038\/s41586-026-11167-2","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:43:24Z","timestamp":1792039404000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational design of metalloproteases"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9857-0594","authenticated-orcid":false,"given":"Anqi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4532-4290","authenticated-orcid":false,"given":"Kejia","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8035-1552","authenticated-orcid":false,"given":"Hojae","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preetham","family":"Venkatesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7557-7985","authenticated-orcid":false,"given":"Samuel J.","family":"Pellock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Hanikel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hojeong","family":"shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-3320","authenticated-orcid":false,"given":"Kieran","family":"Didi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1935-236X","authenticated-orcid":false,"given":"Lars L.","family":"Schaaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-3896","authenticated-orcid":false,"given":"Cristina","family":"D\u00edaz-Perlas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6910-6255","authenticated-orcid":false,"given":"Brian","family":"Coventry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8097-3675","authenticated-orcid":false,"given":"Donghyo","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0510-8240","authenticated-orcid":false,"given":"Seth M.","family":"Woodbury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8109-7929","authenticated-orcid":false,"given":"Pengfei","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9403-6631","authenticated-orcid":false,"given":"Shingo","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9473-2912","authenticated-orcid":false,"given":"Asim K.","family":"Bera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-4004","authenticated-orcid":false,"given":"Hannah","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5487-0499","authenticated-orcid":false,"given":"Alex","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2223-2687","authenticated-orcid":false,"given":"Yanqing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0313-6248","authenticated-orcid":false,"given":"Stacey","family":"Gerben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lemuel","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjam\u00ed","family":"Oller-Salvia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0851-704X","authenticated-orcid":false,"given":"Anthony A.","family":"Hyman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3941-621X","authenticated-orcid":false,"given":"Donald","family":"Hilvert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7896-6217","authenticated-orcid":false,"given":"David","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,14]]},"reference":[{"key":"11167_CR1","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1126\/science.aau3744","volume":"362","author":"S Studer","year":"2018","unstructured":"Studer, S. et al. Evolution of a highly active and enantiospecific metalloenzyme from short peptides. Science 362, 1285\u20131288 (2018).","journal-title":"Science"},{"key":"11167_CR2","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/s41586-025-09746-w","volume":"649","author":"D Kim","year":"2026","unstructured":"Kim, D. et al. Computational design of metallohydrolases. Nature 649, 246\u2013253 (2026).","journal-title":"Nature"},{"key":"11167_CR3","doi-asserted-by":"publisher","unstructured":"Bauer, M. S. et al. design of phospho-tyrosine peptide binders. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2025.09.29.678898 (2025).","DOI":"10.1101\/2025.09.29.678898"},{"key":"11167_CR4","doi-asserted-by":"publisher","unstructured":"Butcher, J. et al. Design of all-atom biomolecular interactions with RFdiffusion3. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2025.09.18.676967 (2025).","DOI":"10.1101\/2025.09.18.676967"},{"key":"11167_CR5","doi-asserted-by":"publisher","first-page":"6105","DOI":"10.1021\/ja954077c","volume":"118","author":"A Radzicka","year":"1996","unstructured":"Radzicka, A. & Richard, W. Rates of uncatalyzed peptide bond hydrolysis in neutral solution and the transition state affinities of proteases. J. Am. Chem. Soc. 118, 6105\u20136109 (1996).","journal-title":"J. Am. Chem. Soc."},{"key":"11167_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0014-5793(94)01079-X","volume":"354","author":"NM Hooper","year":"1994","unstructured":"Hooper, N. M. Families of zinc metalloproteases. FEBS Lett. 354, 1\u20136 (1994).","journal-title":"FEBS Lett."},{"key":"11167_CR7","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1021\/cr950042j","volume":"96","author":"WN Lipscomb","year":"1996","unstructured":"Lipscomb, W. N. & Str\u00e4ter, N. Recent advances in zinc enzymology. Chem. Rev. 96, 2375\u20132434 (1996).","journal-title":"Chem. Rev."},{"key":"11167_CR8","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1124\/pharmrev.121.000349","volume":"74","author":"LGN de Almeida","year":"2022","unstructured":"de Almeida, L. G. N. et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharmacol. Rev. 74, 714\u2013770 (2022).","journal-title":"Pharmacol. Rev."},{"key":"11167_CR9","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/nrm2125","volume":"8","author":"A Page-McCaw","year":"2007","unstructured":"Page-McCaw, A., Ewald, A. J. & Werb, Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8, 221\u2013233 (2007).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"11167_CR10","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.mam.2008.08.001","volume":"29","author":"DR Edwards","year":"2008","unstructured":"Edwards, D. R., Handsley, M. M. & Pennington, C. J. The ADAM metalloproteinases. Mol. Aspects Med. 29, 258\u2013289 (2008).","journal-title":"Mol. Aspects Med."},{"key":"11167_CR11","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1038\/s41420-023-01744-z","volume":"9","author":"Z Wang","year":"2023","unstructured":"Wang, Z., Li, W., Chen, S. & Tang, X. X. Role of ADAM and ADAMTS proteases in pathological tissue remodeling. Cell Death Discov. 9, 447 (2023).","journal-title":"Cell Death Discov."},{"key":"11167_CR12","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1038\/hr.2009.74","volume":"32","author":"M Iwai","year":"2009","unstructured":"Iwai, M. & Horiuchi, M. Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis. Hypertens. Res. 32, 533\u2013536 (2009).","journal-title":"Hypertens. Res."},{"key":"11167_CR13","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1007\/s12010-013-0350-8","volume":"170","author":"J Wang","year":"2013","unstructured":"Wang, J., Xu, A., Wan, Y. & Li, Q. Purification and characterization of a new metallo-neutral protease for beer brewing from Bacillus amyloliquefaciens SYB-001. Appl. Biochem. Biotechnol. 170, 2021\u20132033 (2013).","journal-title":"Appl. Biochem. Biotechnol."},{"key":"11167_CR14","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.4103\/0972-2327.83099","volume":"14","author":"A Jabeen","year":"2011","unstructured":"Jabeen, A., Kandadai, R. M., Kannikannan, M. A. & Borgohain, R. Guidelines for the use of botulinum toxin in movement disorders and spasticity. Ann. Indian Acad. Neurol. 14, S31\u2013S34 (2011).","journal-title":"Ann. Indian Acad. Neurol."},{"key":"11167_CR15","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/S0302-2838(03)00250-1","volume":"44","author":"T Leippold","year":"2003","unstructured":"Leippold, T., Reitz, A. & Schurch, B. Botulinum toxin as a new therapy option for voiding disorders: current state of the art. Eur. Urol. 44, 165\u2013174 (2003).","journal-title":"Eur. Urol."},{"key":"11167_CR16","doi-asserted-by":"publisher","first-page":"223","DOI":"10.2147\/CCID.S202919","volume":"12","author":"BK Satriyasa","year":"2019","unstructured":"Satriyasa, B. K. Botulinum toxin (Botox) A for reducing the appearance of facial wrinkles: a literature review of clinical use and pharmacological aspect. Clin. Cosmet. Investig. Dermatol. 12, 223\u2013228 (2019).","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"11167_CR17","doi-asserted-by":"publisher","first-page":"3674","DOI":"10.1021\/ja01072a016","volume":"86","author":"B Zerner","year":"1964","unstructured":"Zerner, B., Bond, R. P. M. & Bender, M. L. Kinetic evidence for the formation of acyl-enzyme intermediates in the \u03b1-chymotrypsin-catalyzed hydrolyses of specific substrates. J. Am. Chem. Soc. 86, 3674\u20133679 (1964).","journal-title":"J. Am. Chem. Soc."},{"key":"11167_CR18","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1021\/ar00156a004","volume":"21","author":"FG Bordwell","year":"1988","unstructured":"Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide solution. Acc. Chem. Res. 21, 456\u2013463 (1988).","journal-title":"Acc. Chem. Res."},{"key":"11167_CR19","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fimmu.2015.00123","volume":"6","author":"N Nagy","year":"2015","unstructured":"Nagy, N. et al. 4-methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy in inflammation, autoimmunity, and cancer. Front. Immunol. 6, 123 (2015).","journal-title":"Front. Immunol."},{"key":"11167_CR20","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3390\/molecules28020601","volume":"28","author":"S Bailey-Darland","year":"2023","unstructured":"Bailey-Darland, S., Krueger, T. D. & Fang, C. Ultrafast spectroscopies of nitrophenols and nitrophenolates in solution: from electronic dynamics and vibrational structures to photochemical and environmental implications. Molecules 28, 601 (2023).","journal-title":"Molecules"},{"key":"11167_CR21","doi-asserted-by":"publisher","first-page":"E2615","DOI":"10.3390\/molecules23102615","volume":"23","author":"S Mahesh","year":"2018","unstructured":"Mahesh, S., Tang, K.-C. & Raj, M. Amide bond activation of biological molecules. Molecules 23, E2615 (2018).","journal-title":"Molecules"},{"key":"11167_CR22","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1038\/s41586-023-06415-8","volume":"620","author":"JL Watson","year":"2023","unstructured":"Watson, J. L. et al. De novo design of protein structure and function with RFdiffusion. Nature 620, 1089\u20131100 (2023).","journal-title":"Nature"},{"key":"11167_CR23","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1126\/science.adp1779","volume":"386","author":"M Gl\u00f6gl","year":"2024","unstructured":"Gl\u00f6gl, M. et al. Target-conditioned diffusion generates potent TNFR superfamily antagonists and agonists. Science 386, 1154\u20131161 (2024).","journal-title":"Science"},{"key":"11167_CR24","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/s41586-024-08393-x","volume":"639","author":"S V\u00e1zquez Torres","year":"2025","unstructured":"V\u00e1zquez Torres, S. et al. De novo designed proteins neutralize lethal snake venom toxins. Nature 639, 225\u2013231 (2025).","journal-title":"Nature"},{"key":"11167_CR25","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/s41586-025-09721-5","volume":"649","author":"NR Bennett","year":"2026","unstructured":"Bennett, N. R. et al. Atomically accurate de novo design of antibodies with RFdiffusion. Nature 649, 183\u2013193 (2026).","journal-title":"Nature"},{"key":"11167_CR26","doi-asserted-by":"publisher","first-page":"8140","DOI":"10.1021\/jm501071f","volume":"57","author":"S Vassiliou","year":"2014","unstructured":"Vassiliou, S. et al. Structure-guided, single-point modifications in the phosphinic dipeptide structure yield highly potent and selective inhibitors of neutral aminopeptidases. J. Med. Chem. 57, 8140\u20138151 (2014).","journal-title":"J. Med. Chem."},{"key":"11167_CR27","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","volume":"630","author":"J Abramson","year":"2024","unstructured":"Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493\u2013500 (2024).","journal-title":"Nature"},{"key":"11167_CR28","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nsb0896-671","volume":"3","author":"F Grams","year":"1996","unstructured":"Grams, F. et al. Structure of astacin with a transition-state analogue inhibitor. Nat. Struct. Biol. 3, 671\u2013675 (1996).","journal-title":"Nat. Struct. Biol."},{"key":"11167_CR29","doi-asserted-by":"publisher","unstructured":"Xue, F. et al. Improving protein sequence design through Designability Preference Optimization. Preprint at https:\/\/doi.org\/10.48550\/arXiv.2506.00297 (2025).","DOI":"10.48550\/arXiv.2506.00297"},{"key":"11167_CR30","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj7662","volume":"375","author":"DD Sahtoe","year":"2022","unstructured":"Sahtoe, D. D. et al. Reconfigurable asymmetric protein assemblies through implicit negative design. Science 375, eabj7662 (2022).","journal-title":"Science"},{"key":"11167_CR31","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1111\/j.1432-1033.1986.tb09664.x","volume":"157","author":"DE Tronrud","year":"1986","unstructured":"Tronrud, D. E., Monzingo, A. F. & Matthews, B. W. Crystallographic structural analysis of phosphoramidates as inhibitors and transition-state analogs of thermolysin. Eur. J. Biochem. 157, 261\u2013268 (1986).","journal-title":"Eur. J. Biochem."},{"key":"11167_CR32","doi-asserted-by":"publisher","first-page":"8171","DOI":"10.1021\/bi00247a012","volume":"30","author":"H Kim","year":"1991","unstructured":"Kim, H. & Lipscomb, W. N. Comparison of the structures of three carboxypeptidase A-phosphonate complexes determined by X-ray crystallography. Biochemistry 30, 8171\u20138180 (1991).","journal-title":"Biochemistry"},{"key":"11167_CR33","doi-asserted-by":"publisher","first-page":"4618","DOI":"10.1021\/bi00289a002","volume":"22","author":"PA Bartlett","year":"1983","unstructured":"Bartlett, P. A. & Marlowe, C. K. Phosphonamidates as transition-state analogue inhibitors of thermolysin. Biochemistry 22, 4618\u20134624 (1983).","journal-title":"Biochemistry"},{"key":"11167_CR34","doi-asserted-by":"publisher","first-page":"14208","DOI":"10.1021\/jacs.3c04047","volume":"145","author":"AM Hoffnagle","year":"2023","unstructured":"Hoffnagle, A. M. & Tezcan, F. A. Atomically accurate design of metalloproteins with predefined coordination geometries. J. Am. Chem. Soc. 145, 14208\u201314214 (2023).","journal-title":"J. Am. Chem. Soc."},{"key":"11167_CR35","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1021\/ja208015j","volume":"134","author":"BS Der","year":"2012","unstructured":"Der, B. S. et al. Metal-mediated affinity and orientation specificity in a computationally designed protein homodimer. J. Am. Chem. Soc. 134, 375\u2013385 (2012).","journal-title":"J. Am. Chem. Soc."},{"key":"11167_CR36","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/0003-9861(88)90137-3","volume":"265","author":"JR Schullek","year":"1988","unstructured":"Schullek, J. R. & Wilson, I. B. The binding of zinc to angiotensin-converting enzyme. Arch. Biochem. Biophys. 265, 346\u2013350 (1988).","journal-title":"Arch. Biochem. Biophys."},{"key":"11167_CR37","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/s41587-023-01773-0","volume":"42","author":"M van Kempen","year":"2024","unstructured":"van Kempen, M. et al. Fast and accurate protein structure search with Foldseek. Nat. Biotechnol. 42, 243\u2013246 (2024).","journal-title":"Nat. Biotechnol."},{"key":"11167_CR38","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1006\/abbi.1994.1150","volume":"310","author":"RL Wolz","year":"1994","unstructured":"Wolz, R. L. A kinetic comparison of the homologous proteases astacin and meprin A. Arch. Biochem. Biophys. 310, 144\u2013151 (1994).","journal-title":"Arch. Biochem. Biophys."},{"key":"11167_CR39","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1006\/abio.1993.1145","volume":"210","author":"JW Ryan","year":"1993","unstructured":"Ryan, J. W. et al. A radiochemical assay for aminopeptidase N. Anal. Biochem. 210, 27\u201333 (1993).","journal-title":"Anal. Biochem."},{"key":"11167_CR40","doi-asserted-by":"publisher","unstructured":"Batatia, I. et al. MACE-POLAR-1: a polarisable electrostatic foundation model for molecular chemistry. Preprint at https:\/\/doi.org\/10.48550\/arXiv.2602.19411 (2026).","DOI":"10.48550\/arXiv.2602.19411"},{"key":"11167_CR41","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.jinorgbio.2012.02.029","volume":"111","author":"S-L Chen","year":"2012","unstructured":"Chen, S.-L., Li, Z.-S. & Fang, W.-H. Theoretical investigation of astacin proteolysis. J. Inorg. Biochem. 111, 70\u201379 (2012).","journal-title":"J. Inorg. Biochem."},{"key":"11167_CR42","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/S0006-291X(02)00574-0","volume":"294","author":"RB Kapust","year":"2002","unstructured":"Kapust, R. B., T\u00f6zs\u00e9r, J., Copeland, T. D. & Waugh, D. S. The P1\u2019 specificity of tobacco etch virus protease. Biochem. Biophys. Res. Commun. 294, 949\u2013955 (2002).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"11167_CR43","doi-asserted-by":"publisher","first-page":"131066","DOI":"10.1016\/j.ijbiomac.2024.131066","volume":"265","author":"M Mei","year":"2024","unstructured":"Mei, M. et al. A combinatorial strategy for HRV 3C protease engineering to achieve the N-terminal free cleavage. Int. J. Biol. Macromol. 265, 131066 (2024).","journal-title":"Int. J. Biol. Macromol."},{"key":"11167_CR44","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1016\/j.jmb.2006.05.041","volume":"360","author":"B Fang","year":"2006","unstructured":"Fang, B., Boross, P. I., Tozser, J. & Weber, I. T. Structural and kinetic analysis of caspase-3 reveals role for s5 binding site in substrate recognition. J. Mol. Biol. 360, 654\u2013666 (2006).","journal-title":"J. Mol. Biol."},{"key":"11167_CR45","doi-asserted-by":"publisher","first-page":"10316","DOI":"10.1073\/pnas.112332899","volume":"99","author":"ES Radisky","year":"2002","unstructured":"Radisky, E. S. & Koshland, D. E. Jr. A clogged gutter mechanism for protease inhibitors. Proc. Natl Acad. Sci. USA 99, 10316\u201310321 (2002).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"11167_CR46","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1016\/S0014-5793(00)02163-3","volume":"484","author":"I Yiallouros","year":"2000","unstructured":"Yiallouros, I., Grosse Berkhoff, E. & St\u00f6cker, W. The roles of Glu93 and Tyr149 in astacin-like zinc peptidases. FEBS Lett. 484, 224\u2013228 (2000).","journal-title":"FEBS Lett."},{"key":"11167_CR47","doi-asserted-by":"publisher","first-page":"16803","DOI":"10.1074\/jbc.270.28.16803","volume":"270","author":"A Beaumont","year":"1995","unstructured":"Beaumont, A. et al. The role of histidine 231 in thermolysin-like enzymes. A site-directed mutagenesis study. J. Biol. Chem. 270, 16803\u201316808 (1995).","journal-title":"J. Biol. Chem."},{"key":"11167_CR48","doi-asserted-by":"publisher","first-page":"20692","DOI":"10.1016\/S0021-9258(17)30559-8","volume":"265","author":"MA Phillips","year":"1990","unstructured":"Phillips, M. A., Fletterick, R. & Rutter, W. J. Arginine 127 stabilizes the transition state in carboxypeptidase. J. Biol. Chem. 265, 20692\u201320698 (1990).","journal-title":"J. Biol. Chem."},{"key":"11167_CR49","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/j.1432-1033.1982.tb05919.x","volume":"124","author":"S Kunugi","year":"1982","unstructured":"Kunugi, S., Hirohara, H. & Ise, N. pH and temperature dependences of thermolysin catalysis. Catalytic role of zinc-coordinated water. Eur. J. Biochem. 124, 157\u2013163 (1982).","journal-title":"Eur. J. Biochem."},{"key":"11167_CR50","doi-asserted-by":"publisher","first-page":"11026","DOI":"10.1074\/jbc.275.15.11026","volume":"275","author":"LL Johnson","year":"2000","unstructured":"Johnson, L. L. et al. A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition. J. Biol. Chem. 275, 11026\u201311033 (2000).","journal-title":"J. Biol. Chem."},{"key":"11167_CR51","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.bbrc.2006.10.093","volume":"351","author":"T Arai","year":"2006","unstructured":"Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602\u2013611 (2006).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"11167_CR52","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1146\/annurev-pathol-020712-163913","volume":"10","author":"GT Westermark","year":"2015","unstructured":"Westermark, G. T., F\u00e4ndrich, M. & Westermark, P. AA amyloidosis: pathogenesis and targeted therapy. Annu. Rev. Pathol. 10, 321\u2013344 (2015).","journal-title":"Annu. Rev. Pathol."},{"key":"11167_CR53","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1007\/s11055-017-0513-0","volume":"47","author":"OS Levin","year":"2017","unstructured":"Levin, O. S. & Vasenina, E. E. 25 years of the amyloid hypothesis of the origin of Alzheimer\u2019s disease: advances, failures, and new perspectives. Neurosci. Behav. Physiol. 47, 1065\u20131070 (2017).","journal-title":"Neurosci. Behav. Physiol."},{"key":"11167_CR54","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41594-018-0064-2","volume":"25","author":"EL Guenther","year":"2018","unstructured":"Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 25, 463\u2013471 (2018).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"11167_CR55","doi-asserted-by":"publisher","first-page":"6306","DOI":"10.1074\/jbc.RA118.007222","volume":"294","author":"WM Babinchak","year":"2019","unstructured":"Babinchak, W. M. et al. The role of liquid\u2013liquid phase separation in aggregation of the TDP-43 low-complexity domain. J. Biol. Chem. 294, 6306\u20136317 (2019).","journal-title":"J. Biol. Chem."},{"key":"11167_CR56","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.addr.2017.09.009","volume":"118","author":"SK Sharma","year":"2017","unstructured":"Sharma, S. K. & Bagshawe, K. D. Antibody directed enzyme prodrug therapy (ADEPT): trials and tribulations. Adv. Drug Deliv. Rev. 118, 2\u20137 (2017).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"11167_CR57","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/s41586-018-0830-7","volume":"565","author":"D-A Silva","year":"2019","unstructured":"Silva, D.-A. et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature 565, 186\u2013191 (2019).","journal-title":"Nature"},{"key":"11167_CR58","doi-asserted-by":"publisher","unstructured":"Shin, H. et al. De novo design of protease-activatable cytokine prodrugs. Preprint at bioRxiv https:\/\/doi.org\/10.64898\/2026.09.19.752834.","DOI":"10.64898\/2026.09.19.752834"},{"key":"11167_CR59","first-page":"4062","volume":"63","author":"AM Mansour","year":"2003","unstructured":"Mansour, A. M. et al. A new approach for the treatment of malignant melanoma: enhanced antitumor efficacy of an albumin-binding doxorubicin prodrug that is cleaved by matrix metalloproteinase 2. Cancer Res. 63, 4062\u20134066 (2003).","journal-title":"Cancer Res."},{"key":"11167_CR60","doi-asserted-by":"publisher","first-page":"45495","DOI":"10.1021\/jacs.5c16108","volume":"147","author":"M Escobar-Rosales","year":"2025","unstructured":"Escobar-Rosales, M. et al. De novo design of peptide masks enables rapid generation of conditionally-active miniprotein binders. J. Am. Chem. Soc. 147, 45495\u201345505 (2025).","journal-title":"J. Am. Chem. Soc."},{"key":"11167_CR61","doi-asserted-by":"publisher","first-page":"E4148","DOI":"10.1073\/pnas.1406134111","volume":"111","author":"BI Ratnikov","year":"2014","unstructured":"Ratnikov, B. I. et al. Basis for substrate recognition and distinction by matrix metalloproteinases. Proc. Natl Acad. Sci. USA 111, E4148\u2013E4155 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"11167_CR62","doi-asserted-by":"publisher","unstructured":"Chen, A. Computational design of metalloproteases. Zenodo https:\/\/doi.org\/10.5281\/zenodo.22654831 (2026).","DOI":"10.5281\/zenodo.22654831"}],"container-title":["Nature"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-11167-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-11167-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-11167-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T19:02:29Z","timestamp":1794337349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41586-026-11167-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,14]]},"references-count":62,"alternative-id":["11167"],"URL":"https:\/\/doi.org\/10.1038\/s41586-026-11167-2","relation":{},"ISSN":["0028-0836","1476-4687"],"issn-type":[{"value":"0028-0836","type":"print"},{"value":"1476-4687","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,14]]},"assertion":[{"value":"14 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Provisional patent applications 64\/047,504 and 63\/921,483 have been filed related to aspects of the methods and designs described in this work, listing A.C., K.W., H.C., P.V., S.J.P., D.H., A.K.B. and D.B. as inventors or contributors. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}