8e4w
From Proteopedia
(Difference between revisions)
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==Crystal Structure of SARS CoV-2 Mpro mutant N142P with Pfizer Intravenous Inhibitor PF-00835231== | ==Crystal Structure of SARS CoV-2 Mpro mutant N142P with Pfizer Intravenous Inhibitor PF-00835231== | ||
| - | <StructureSection load='8e4w' size='340' side='right'caption='[[8e4w]]' scene=''> | + | <StructureSection load='8e4w' size='340' side='right'caption='[[8e4w]], [[Resolution|resolution]] 2.75Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E4W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E4W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[8e4w]] is a 2 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=8E4W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E4W FirstGlance]. <br> |
| - | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.75Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V2M:~{N}-[(2~{S})-1-[[(2~{S},3~{S})-3,4-bis(oxidanyl)-1-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]butan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]-4-methoxy-1~{H}-indole-2-carboxamide'>V2M</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=8e4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e4w OCA], [https://pdbe.org/8e4w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e4w RCSB], [https://www.ebi.ac.uk/pdbsum/8e4w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e4w ProSAT]</span></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=8e4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e4w OCA], [https://pdbe.org/8e4w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e4w RCSB], [https://www.ebi.ac.uk/pdbsum/8e4w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e4w ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The appearance and spread of mutations that cause drug resistance in rapidly evolving diseases, including infections by the SARS-CoV-2 virus, are major concerns for human health. Many drugs target enzymes, and resistance-conferring mutations impact inhibitor binding or enzyme activity. Nirmatrelvir, the most widely used inhibitor currently used to treat SARS-CoV-2 infections, targets the main protease (M(pro)) preventing it from processing the viral polyprotein into active subunits. Our previous work systematically analyzed resistance mutations in M(pro) that reduce binding to inhibitors; here, we investigate mutations that affect enzyme function. Hyperactive mutations that increase M(pro) activity can contribute to drug resistance but have not been thoroughly studied. To explore how hyperactive mutations contribute to resistance, we comprehensively assessed how all possible individual mutations in M(pro) affect enzyme function using a mutational scanning approach with a fluorescence resonance energy transfer (FRET)-based yeast readout. We identified hundreds of mutations that significantly increased the M(pro) activity. Hyperactive mutations occurred both proximal and distal to the active site, consistent with protein stability and/or dynamics impacting activity. Hyperactive mutations were observed 3 times more than mutations which reduced apparent binding to nirmatrelvir in recent studies of laboratory-grown viruses selected for drug resistance. Hyperactive mutations were also about three times more prevalent than nirmatrelvir binding mutations in sequenced isolates from circulating SARS-CoV-2. Our findings indicate that hyperactive mutations are likely to contribute to the natural evolution of drug resistance in M(pro) and provide a comprehensive list for future surveillance efforts. | ||
| + | |||
| + | Contributions of Hyperactive Mutations in M(pro) from SARS-CoV-2 to Drug Resistance.,Flynn JM, Zvornicanin SN, Tsepal T, Shaqra AM, Kurt Yilmaz N, Jia W, Moquin S, Dovala D, Schiffer CA, Bolon DNA ACS Infect Dis. 2024 Apr 12;10(4):1174-1184. doi: 10.1021/acsinfecdis.3c00560. , Epub 2024 Mar 12. PMID:38472113<ref>PMID:38472113</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8e4w" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: | + | [[Category: Severe acute respiratory syndrome coronavirus 2]] |
| + | [[Category: Schiffer CA]] | ||
| + | [[Category: Shaqra AM]] | ||
Current revision
Crystal Structure of SARS CoV-2 Mpro mutant N142P with Pfizer Intravenous Inhibitor PF-00835231
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