View source for 8h7w


==Crystal structure of SARS-CoV-2 main protease (Mpro) Mutant (S144A) in complex with protease inhibitor Nirmatrelvir==
<StructureSection load='8h7w' size='340' side='right'caption='[[8h7w]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8h7w]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8H7W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8H7W FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4WI:(1~{R},2~{S},5~{S})-~{N}-[(2~{S})-1-azanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]-3-[(2~{S})-3,3-dimethyl-2-[2,2,2-tris(fluoranyl)ethanoylamino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide'>4WI</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8h7w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8h7w OCA], [https://pdbe.org/8h7w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8h7w RCSB], [https://www.ebi.ac.uk/pdbsum/8h7w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8h7w ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
Nirmatrelvir is a specific antiviral drug that targets the main protease (M(pro)) of SARS-CoV-2 and has been approved to treat COVID-19(1,2). As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations(3). The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of M(pro) can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 M(pro) mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously(3). Such a profile was also observed for ensitrelvir, another clinically relevant M(pro) inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation M(pro) inhibitors.

Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir.,Duan Y, Zhou H, Liu X, Iketani S, Lin M, Zhang X, Bian Q, Wang H, Sun H, Hong SJ, Culbertson B, Mohri H, Luck MI, Zhu Y, Liu X, Lu Y, Yang X, Yang K, Sabo Y, Chavez A, Goff SP, Rao Z, Ho DD, Yang H Nature. 2023 Oct;622(7982):376-382. doi: 10.1038/s41586-023-06609-0. Epub 2023 , Sep 11. PMID:37696289<ref>PMID:37696289</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 8h7w" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Lin M]]
[[Category: Liu X]]