{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:37:34Z","timestamp":1787567854251,"version":"build-2736575974"},"reference-count":100,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM143000"],"award-info":[{"award-number":["R35 GM143000"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM127040"],"award-info":[{"award-number":["R35 GM127040"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM133395"],"award-info":[{"award-number":["T32 GM133395"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20 GM104316"],"award-info":[{"award-number":["P20 GM104316"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10 OD026896A"],"award-info":[{"award-number":["S10 OD026896A"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-20-CE15-0020-01"],"award-info":[{"award-number":["ANR-20-CE15-0020-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"name":"French Research Agency on HIV and Emerging Infectious Diseases ANRS\/MIE","award":["ECTZ118944"],"award-info":[{"award-number":["ECTZ118944"]}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    The SARS-CoV-2 main protease (M\n                    <jats:sup>pro<\/jats:sup>\n                    or Nsp5) is critical for production of viral proteins during infection and, like many viral proteases, also targets host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 is recognized and cleaved by SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    . TRMT1 installs the\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    ,\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    -dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes cellular protein synthesis and redox homeostasis. We find that M\n                    <jats:sup>pro<\/jats:sup>\n                    can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. Evolutionary analysis shows the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. TRMT1 proteolysis results in reduced tRNA binding and elimination of tRNA methyltransferase activity. We also determined the structure of an M\n                    <jats:sup>pro<\/jats:sup>\n                    -TRMT1 peptide complex that shows how TRMT1 engages the M\n                    <jats:sup>pro<\/jats:sup>\n                    active site in an uncommon substrate binding conformation. Finally, enzymology and molecular dynamics simulations indicate that kinetic discrimination occurs during a later step of M\n                    <jats:sup>pro<\/jats:sup>\n                    -mediated proteolysis following substrate binding. Together, these data provide new insights into substrate recognition by SARS-CoV-2 M\n                    <jats:sup>pro<\/jats:sup>\n                    that could help guide future antiviral therapeutic development and show how proteolysis of TRMT1 during SARS-CoV-2 infection impairs both TRMT1 tRNA binding and tRNA modification activity to disrupt host translation and potentially impact COVID-19 pathogenesis or phenotypes.\n                  <\/jats:p>","DOI":"10.7554\/elife.91168","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T10:04:39Z","timestamp":1700042679000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91168","source":"Crossref","is-referenced-by-count":2,"title":["Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5944-9609","authenticated-orcid":true,"given":"Angel","family":"D'Oliviera","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01sbq1a82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry & Biochemistry, University of Delaware","place":["Newark, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6712-8737","authenticated-orcid":true,"given":"Xuhang","family":"Dai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, New York University","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9409-3302","authenticated-orcid":true,"given":"Saba","family":"Mottaghinia","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059sz6q14","id-type":"ROR","asserted-by":"publisher"}],"name":"CIRI (Centre International de Recherche en Infectiologie), Univ Lyon, Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon","place":["Lyon, France"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Sophie","family":"Olson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01sbq1a82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry & Biochemistry, University of Delaware","place":["Newark, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Evan P","family":"Geissler","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01sbq1a82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry & Biochemistry, University of Delaware","place":["Newark, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-7534","authenticated-orcid":true,"given":"Lucie","family":"Etienne","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059sz6q14","id-type":"ROR","asserted-by":"publisher"}],"name":"CIRI (Centre International de Recherche en Infectiologie), Univ Lyon, Inserm, U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon","place":["Lyon, France"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4984-3354","authenticated-orcid":true,"given":"Yingkai","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, New York University","place":["New York, United States"]},{"id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"publisher"}],"name":"Simons Center for Computational Physical Chemistry at New York University","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1553-3008","authenticated-orcid":true,"given":"Jeffrey S","family":"Mugridge","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01sbq1a82","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry & Biochemistry, University of Delaware","place":["Newark, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00769-18","type":"journal-article","article-title":"Smc5\/6 antagonism by hbx is an evolutionarily conserved function of hepatitis b virus infection in mammals","volume":"92","author":"Abdul","year":"2018","journal-title":"Journal of Virology"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27082523","type":"journal-article","article-title":"Advances in the development of SARS-CoV-2 mpro inhibitors","volume":"27","author":"Agost-Beltr\u00e1n","year":"2022","journal-title":"Molecules"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/0021-9991(83)90014-1","type":"journal-article","article-title":"Rattle: a \u201cvelocity\u201d version of the shake algorithm for molecular dynamics calculations","volume":"52","author":"Andersen","year":"1983","journal-title":"Journal of Computational Physics"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1002\/jmv.26814","type":"journal-article","article-title":"Targeting SARS\u2010CoV\u20102 viral proteases as a therapeutic strategy to treat COVID\u201019","volume":"93","author":"Anirudhan","year":"2021","journal-title":"Journal of Medical Virology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/j.cell.2020.10.004","type":"journal-article","article-title":"SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses","volume":"183","author":"Banerjee","year":"2020","journal-title":"Cell"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1101\/gr.1865504","type":"journal-article","article-title":"Genewise and genomewise","volume":"14","author":"Birney","year":"2004","journal-title":"Genome Research"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1002\/ajmg.a.38631","type":"journal-article","article-title":"Mutations in the tRNA methyltransferase 1 gene TRMT1 cause congenital microcephaly, isolated inferior vermian hypoplasia and cystic leukomalacia in addition to intellectual disability","volume":"176","author":"Blaesius","year":"2018","journal-title":"American Journal of Medical Genetics Part A"},{"key":"bib8","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202200016","type":"journal-article","article-title":"Mass spectrometric assays reveal discrepancies in inhibition profiles for the sars-cov-2 papain-like protease","volume":"17","author":"Brewitz","year":"2022","journal-title":"ChemMedChem"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1002\/9781119789741","type":"book-chapter","article-title":"Pharmacologic therapeutics for COVID-19","volume-title":"Coronavirus Disease 2019","author":"Burkhardt","year":"2023"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"D437","DOI":"10.1093\/nar\/gkaa1038","type":"journal-article","article-title":"RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences","volume":"49","author":"Burley","year":"2021","journal-title":"Nucleic Acids Research"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206610119","type":"journal-article","article-title":"Distinct evolutionary trajectories of SARS-CoV-2-interacting proteins in bats and primates identify important host determinants of COVID-19","volume":"119","author":"Cariou","year":"2022","journal-title":"PNAS"},{"key":"bib12","volume-title":"AMBER 2020: University of California","author":"Case","year":"2020","type":"book"},{"key":"bib13","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2020.110102","type":"journal-article","article-title":"SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression","volume":"143","author":"Cecchini","year":"2020","journal-title":"Medical Hypotheses"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"e00049","DOI":"10.1128\/jvi.00049-24","type":"journal-article","article-title":"Optimization of quenched fluorescent peptide substrates of SARS-CoV-2 3CL pro main protease (Mpro) from proteomic identification of P6\u2014P6\u2019 active site specificity","volume":"98","author":"Cesar Ramos de Jesus","year":"2024","journal-title":"Journal of Virology"},{"key":"bib15","type":"web-resource","article-title":"COVID-19 Dashboard","author":"C. for S. Science, E","year":"2023","unstructured":"C. for S. Science, E. 2023. COVID-19 Dashboard. https:\/\/coronavirus.jhu.edu\/map.html [Accessed October 3, 2023]."},{"key":"bib16","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1016\/j.molcel.2017.11.002","type":"journal-article","article-title":"Transcriptome-wide analysis of roles for tRNA modifications in translational regulation","volume":"68","author":"Chou","year":"2017","journal-title":"Molecular Cell"},{"key":"bib17","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2022.101144","type":"journal-article","article-title":"Diagnostic and therapeutic potential of protease inhibition","volume":"88","author":"Cwilichowska","year":"2022","journal-title":"Molecular Aspects of Medicine"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1063\/1.464397","type":"journal-article","article-title":"Particle mesh Ewald: An N\u22c5log(N) method for Ewald sums in large systems","volume":"98","author":"Darden","year":"1993","journal-title":"The Journal of Chemical Physics"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129631","type":"journal-article","article-title":"The role of a novel trmt1 gene mutation and rare grm1 gene defect in intellectual disability in two azeri families","volume":"10","author":"Davarniya","year":"2015","journal-title":"PLOS ONE"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"12502","DOI":"10.1093\/nar\/gkaa1116","type":"journal-article","article-title":"Translational control of coronaviruses","volume":"48","author":"de Breyne","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"bib21","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00214-17","type":"journal-article","article-title":"TRMT1-catalyzed trna modifications are required for redox homeostasis to ensure proper cellular proliferation and oxidative stress survival","volume":"37","author":"Dewe","year":"2017","journal-title":"Molecular and Cellular Biology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","type":"journal-article","article-title":"Features and development of Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallographica. Section D, Biological Crystallography"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12469","type":"journal-article","article-title":"Viruses are a dominant driver of protein adaptation in mammals","volume":"5","author":"Enard","year":"2016","journal-title":"eLife"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1584","DOI":"10.1002\/2211-5463.13413","type":"journal-article","article-title":"Viral and cellular translation during SARS-CoV-2 infection","volume":"12","author":"Eriani","year":"2022","journal-title":"FEBS Open Bio"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1038\/s41586-021-03610-3","type":"journal-article","article-title":"SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis","volume":"594","author":"Finkel","year":"2021","journal-title":"Nature"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.77433","type":"journal-article","article-title":"Comprehensive fitness landscape of SARS-CoV-2 Mpro reveals insights into viral resistance mechanisms","volume":"11","author":"Flynn","year":"2022","journal-title":"eLife"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe9403","type":"journal-article","article-title":"Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms","volume":"370","author":"Gordon","year":"2020","journal-title":"Science"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/s41586-020-2286-9","type":"journal-article","article-title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing","volume":"583","author":"Gordon","year":"2020","journal-title":"Nature"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.1177\/11779322211025876","type":"journal-article","article-title":"Structure and function of major sars-cov-2 and sars-cov proteins","volume":"15","author":"Gorkhali","year":"2021","journal-title":"Bioinformatics and Biology Insights"},{"key":"bib30","type":"web-resource","article-title":"WHO COVID-19 Dashboard","author":"G. W. H. Organization","year":"2023","unstructured":"G. W. H. Organization. 2023. WHO COVID-19 Dashboard. https:\/\/data.who.int\/dashboards\/covid19\/cases [Accessed December 1, 2024]."},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32922-9","type":"journal-article","article-title":"Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro","volume":"13","author":"Hameedi","year":"2022","journal-title":"Nature Communications"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101161118","type":"journal-article","article-title":"Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein","volume":"118","author":"Hsu","year":"2021","journal-title":"PNAS"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1146\/annurev-virology-100114-055014","type":"journal-article","article-title":"A cap-to-tail guide to mrna translation strategies in virus-infected cells","volume":"3","author":"Jan","year":"2016","journal-title":"Annual Review of Virology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","type":"journal-article","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1002\/pro.3280","type":"journal-article","article-title":"Improvements to the APBS biomolecular solvation software suite","volume":"27","author":"Jurrus","year":"2018","journal-title":"Protein Science"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.1186\/s43094-022-00423-7","type":"journal-article","article-title":"Review on development of potential inhibitors of SARS-CoV-2 main protease (MPro)","volume":"8","author":"Katre","year":"2022","journal-title":"Future Journal of Pharmaceutical Sciences"},{"key":"bib37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107367","type":"journal-article","article-title":"Kinetic comparison of all eleven viral polyprotein cleavage site processing events by SARS-CoV-2 main protease using a linked protein FRET platform","volume":"300","author":"Kenward","year":"2024","journal-title":"The Journal of Biological Chemistry"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1093\/molbev\/msz197","type":"journal-article","article-title":"HyPhy 2.5\u2014A customizable platform for evolutionary hypothesis testing using phylogenies","volume":"37","author":"Kosakovsky Pond","year":"2020","journal-title":"Molecular Biology and Evolution"},{"key":"bib39","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202000246","type":"journal-article","article-title":"N-terminomics for the identification of in vitro substrates and cleavage site specificity of the SARS-CoV-2 MAIN PROTEAse","volume":"21","author":"Koudelka","year":"2021","journal-title":"PROTEOMICS"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19662-4","type":"journal-article","article-title":"Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site","volume":"11","author":"Lee","year":"2020","journal-title":"Nature Communications"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1107\/S2059798319011471","type":"journal-article","article-title":"Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix","volume":"75","author":"Liebschner","year":"2019","journal-title":"Acta Crystallographica. Section D, Structural Biology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1006\/abio.1998.3014","type":"journal-article","article-title":"Use of a fluorescence plate reader for measuring kinetic parameters with inner filter effect correction","volume":"267","author":"Liu","year":"1999","journal-title":"Analytical Biochemistry"},{"key":"bib43","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-579","type":"journal-article","article-title":"webPRANK: a phylogeny-aware multiple sequence aligner with interactive alignment browser","volume":"11","author":"L\u00f6ytynoja","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjad024","type":"journal-article","article-title":"SARS-CoV-2 main protease Nsp5 cleaves and inactivates human tRNA methyltransferase TRMT1","volume":"15","author":"Lu","year":"2023","journal-title":"Journal of Molecular Cell Biology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.1021\/acsinfecdis.1c00237","type":"journal-article","article-title":"Recognition of divergent viral substrates by the SARS-CoV-2 main protease","volume":"7","author":"MacDonald","year":"2021","journal-title":"ACS Infectious Diseases"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"W636","DOI":"10.1093\/nar\/gkz268","type":"journal-article","article-title":"The EMBL-EBI search and sequence analysis tools APIs in 2019","volume":"47","author":"Madeira","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","type":"journal-article","article-title":"ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB","volume":"11","author":"Maier","year":"2015","journal-title":"Journal of Chemical Theory and Computation"},{"key":"bib48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25796-w","type":"journal-article","article-title":"Characterising proteolysis during SARS-CoV-2 infection identifies viral cleavage sites and cellular targets with therapeutic potential","volume":"12","author":"Meyer","year":"2021","journal-title":"Nature Communications"},{"key":"bib49","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249523","type":"journal-article","article-title":"Identification of host cellular protein substrates of SARS-COV-2 main protease","volume":"21","author":"Miczi","year":"2020","journal-title":"International Journal of Molecular Sciences"},{"key":"bib50","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2022.2027160","type":"journal-article","article-title":"The efficacy and effectiveness of the COVID-19 vaccines in reducing infection, severity, hospitalization, and mortality: a systematic review","volume":"18","author":"Mohammed","year":"2022","journal-title":"Human Vaccines & Immunotherapeutics"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1080\/22221751.2020.1870414","type":"journal-article","article-title":"SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species","volume":"10","author":"Moustaqil","year":"2021","journal-title":"Emerging Microbes & Infections"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"12997","DOI":"10.1073\/pnas.1601327113","type":"journal-article","article-title":"SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity","volume":"113","author":"Muramatsu","year":"2016","journal-title":"PNAS"},{"key":"bib53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002764","type":"journal-article","article-title":"Detecting individual sites subject to episodic diversifying selection","volume":"8","author":"Murrell","year":"2012","journal-title":"PLOS Genetics"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1093\/molbev\/mst030","type":"journal-article","article-title":"FUBAR: a fast, unconstrained bayesian approximation for inferring selection","volume":"30","author":"Murrell","year":"2013","journal-title":"Molecular Biology and Evolution"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1093\/molbev\/msv035","type":"journal-article","article-title":"Gene-wide identification of episodic selection","volume":"32","author":"Murrell","year":"2015","journal-title":"Molecular Biology and Evolution"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"8085","DOI":"10.1128\/JVI.00972-16","type":"journal-article","article-title":"The evolutionary histories of antiretroviral proteins serinc3 and serinc5 do not support an evolutionary arms race in primates","volume":"90","author":"Murrell","year":"2016","journal-title":"Journal of Virology"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature10423","type":"journal-article","article-title":"Deep sequencing reveals 50 novel genes for recessive cognitive disorders","volume":"478","author":"Najmabadi","year":"2011","journal-title":"Nature"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/bs.aivir.2016.08.001","type":"journal-article","article-title":"Viral and cellular mrna translation in coronavirus-infected cells","volume":"96","author":"Nakagawa","year":"2016","journal-title":"Advances in Virus Research"},{"key":"bib59","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03090-9","type":"journal-article","article-title":"Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay","volume":"5","author":"Narayanan","year":"2022","journal-title":"Communications Biology"},{"key":"bib60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104697","type":"journal-article","article-title":"SARS-CoV-2 polyprotein substrate regulates the stepwise Mpro cleavage reaction","volume":"299","author":"Narwal","year":"2023","journal-title":"The Journal of Biological Chemistry"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109892","type":"journal-article","article-title":"Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CLpro substrate degradome","volume":"37","author":"Pablos","year":"2021","journal-title":"Cell Reports"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","type":"journal-article","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Science"},{"key":"bib63","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa680","type":"journal-article","article-title":"DGINN, an automated and highly-flexible pipeline for the detection of genetic innovations on protein-coding genes","volume":"48","author":"Picard","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"bib64","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00815-22","type":"journal-article","article-title":"The translational landscape of SARS-CoV-2-infected cells reveals suppression of innate immune genes","volume":"13","author":"Puray-Chavez","year":"2022","journal-title":"mBio"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"10316","DOI":"10.1073\/pnas.112332899","type":"journal-article","article-title":"A clogged gutter mechanism for protease inhibitors","volume":"99","author":"Radisky","year":"2002","journal-title":"PNAS"},{"key":"bib66","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.873596","type":"journal-article","article-title":"The effectiveness of COVID-19 vaccines in reducing the incidence, hospitalization, and mortality from COVID-19: a systematic review and meta-analysis","volume":"10","author":"Rahmani","year":"2022","journal-title":"Frontiers in Public Health"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/S1877-1173(09)90009-6","type":"journal-article","article-title":"Viral strategies to subvert the mammalian translation machinery","volume":"90","author":"Roberts","year":"2009","journal-title":"Progress in Molecular Biology and Translational Science"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","type":"journal-article","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nature Methods"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.1107\/S1600577522009377","type":"journal-article","article-title":"AMX - the highly automated macromolecular crystallography (17-ID-1) beamline at the NSLS-II","volume":"29","author":"Schneider","year":"2022","journal-title":"Journal of Synchrotron Radiation"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1093\/molbev\/msz015","type":"journal-article","article-title":"Orthomam v10: scaling-up orthologous coding sequence and exon alignments with more than one hundred mammalian genomes","volume":"36","author":"Scornavacca","year":"2019","journal-title":"Molecular Biology and Evolution"},{"key":"bib71","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31210-w","type":"journal-article","article-title":"Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance","volume":"13","author":"Shaqra","year":"2022","journal-title":"Nature Communications"},{"key":"bib72","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002612","type":"journal-article","article-title":"Thriving under stress: selective translation of HIV-1 structural protein mRNA during Vpr-mediated impairment of eIF4E translation activity","volume":"8","author":"Sharma","year":"2012","journal-title":"PLOS Pathogens"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/s41586-020-2601-5","type":"journal-article","article-title":"Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity","volume":"587","author":"Shin","year":"2020","journal-title":"Nature"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1038\/nrg3905","type":"journal-article","article-title":"Evolutionary insights into host-pathogen interactions from mammalian sequence data","volume":"16","author":"Sironi","year":"2015","journal-title":"Nature Reviews. Genetics"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1093\/molbev\/msv022","type":"journal-article","article-title":"Less is more: an adaptive branch-site random effects model for efficient detection of episodic diversifying selection","volume":"32","author":"Smith","year":"2015","journal-title":"Molecular Biology and Evolution"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1002\/pro.2897","type":"journal-article","article-title":"Epistasis in protein evolution","volume":"25","author":"Starr","year":"2016","journal-title":"Protein Science"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1021\/acsinfecdis.0c00815","type":"journal-article","article-title":"Challenges for targeting sars-cov-2 proteases as a therapeutic strategy for COVID-19","volume":"7","author":"Steuten","year":"2021","journal-title":"ACS Infectious Diseases"},{"key":"bib78","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2021-069317","type":"journal-article","article-title":"Public health impact of covid-19 vaccines in the US: observational study","volume":"377","author":"Suthar","year":"2022","journal-title":"BMJ"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1146\/annurev-immunol-072621-084422","type":"journal-article","article-title":"Evolutionary landscapes of host-virus arms races","volume":"40","author":"Tenthorey","year":"2022","journal-title":"Annual Review of Immunology"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1126\/science.abc8665","type":"journal-article","article-title":"Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2","volume":"369","author":"Thoms","year":"2020","journal-title":"Science"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","type":"journal-article","article-title":"AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"Varadi","year":"2022","journal-title":"Nucleic Acids Research"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1038\/nrmicro2655","type":"journal-article","article-title":"Viral subversion of the host protein synthesis machinery","volume":"9","author":"Walsh","year":"2011","journal-title":"Nature Reviews. Microbiology"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"5264","DOI":"10.1021\/acs.jproteome.1c00289","type":"journal-article","article-title":"Biochemical tools for tracking proteolysis","volume":"20","author":"Wang","year":"2021","journal-title":"Journal of Proteome Research"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1016\/S1473-3099(22)00320-6","type":"journal-article","article-title":"Global impact of the first year of COVID-19 vaccination: a mathematical modelling study","volume":"22","author":"Watson","year":"2022","journal-title":"The Lancet. Infectious Diseases"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1093\/molbev\/msx335","type":"journal-article","article-title":"Datamonkey 2.0: a modern web application for characterizing selective and other evolutionary processes","volume":"35","author":"Weaver","year":"2018","journal-title":"Molecular Biology and Evolution"},{"key":"bib86","doi-asserted-by":"publisher","first-page":"3152","DOI":"10.1016\/j.bpj.2021.06.006","type":"journal-article","article-title":"Transient and stabilized complexes of Nsp7, Nsp8, and Nsp12 in SARS-CoV-2 replication","volume":"120","author":"Wilamowski","year":"2021","journal-title":"Biophysical Journal"},{"key":"bib87","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19770-1","type":"journal-article","article-title":"Architecture of a SARS-CoV-2 mini replication and transcription complex","volume":"11","author":"Yan","year":"2020","journal-title":"Nature Communications"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1016\/j.molcel.2020.10.034","type":"journal-article","article-title":"Nonstructural protein 1 of sars-cov-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA","volume":"80","author":"Yuan","year":"2020","journal-title":"Molecular Cell"},{"key":"bib89","doi-asserted-by":"publisher","DOI":"10.1101\/2022.01.17.476677","type":"preprint","article-title":"Prediction and Validation of Host Cleavage Targets of SARS-CoV-2 3C-like Protease","volume-title":"bioRxiv","author":"Yucel","year":"2022"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1002\/humu.23976","type":"journal-article","article-title":"An intellectual disability\u2010associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity","volume":"41","author":"Zhang","year":"2020","journal-title":"Human Mutation"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.abb3405","type":"journal-article","article-title":"Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved \u03b1-ketoamide inhibitors","volume":"368","author":"Zhang","year":"2020","journal-title":"Science"},{"key":"bib92","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107108118","type":"journal-article","article-title":"Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1","volume":"118","author":"Zhang","year":"2021","journal-title":"PNAS"},{"key":"bib93","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.857490","type":"journal-article","article-title":"Translational control of covid-19 and its therapeutic implication","volume":"13","author":"Zhang","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"bib94","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.90316","type":"journal-article","article-title":"Proteolytic cleavage and inactivation of the TRMT1 tRNA modification enzyme by SARS-CoV-2 main protease","volume":"12","author":"Zhang","year":"2024","journal-title":"eLife"},{"key":"bib95","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2117142119","type":"journal-article","article-title":"Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2","volume":"119","author":"Zhao","year":"2022","journal-title":"PNAS"},{"key":"bib96","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1093\/abbs\/gmab088","type":"journal-article","article-title":"Nsp2 has the potential to be a drug target revealed by global identification of SARS-CoV-2 Nsp2-interacting proteins","volume":"53","author":"Zheng","year":"2021","journal-title":"Acta Biochimica et Biophysica Sinica"},{"key":"bib97","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1021\/acs.jpclett.6b00373","type":"journal-article","article-title":"Amide rotation hindrance predicts proteolytic resistance of cystine-knot peptides","volume":"7","author":"Zhou","year":"2016","journal-title":"The Journal of Physical Chemistry Letters"},{"key":"dataset1","type":"dataset","article-title":"Crystal structure of SARS-CoV-2 main protease (Mpro) C145A mutant in complex with peptide from human tRNA methyltransferase TRMT1","volume-title":"RCSB Protein Data Bank","author":"D'Oliviera","year":"2024","unstructured":"D'Oliviera A, Mugridge JS. 2024. Crystal structure of SARS-CoV-2 main protease (Mpro) C145A mutant in complex with peptide from human tRNA methyltransferase TRMT1. RCSB Protein Data Bank. https:\/\/www.rcsb.org\/structure\/9DW6. 9DW6."},{"key":"dataset2","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.22004474","type":"dataset","article-title":"Primate TRMT1 codon alignment","volume-title":"figshare","author":"Etienne","year":"2023","unstructured":"Etienne L. 2023. Primate TRMT1 codon alignment. figshare."},{"key":"dataset3","doi-asserted-by":"publisher","DOI":"10.6084\/m9.figshare.22004492","type":"dataset","article-title":"Rodent TRMT1 codon alignment","volume-title":"figshare","author":"Etienne","year":"2023","unstructured":"Etienne L. 2023. Rodent TRMT1 codon alignment. figshare."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/91168\/elife-91168-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/91168\/elife-91168-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/91168","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:51:40Z","timestamp":1787565100000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/91168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":100,"alternative-id":["10.7554\/eLife.91168"],"URL":"https:\/\/doi.org\/10.7554\/elife.91168","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.02.20.529306","asserted-by":"subject"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.91168.3","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.91168.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.91168.2","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"accession","id":"9DW6","asserted-by":"subject"},{"id-type":"doi","id":"10.6084\/m9.figshare.22004474","asserted-by":"subject"},{"id-type":"doi","id":"10.6084\/m9.figshare.22004492","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP91168"}}