View source for 8e26


==Crystal Structure of SARS-CoV-2 Main Protease N142S mutant in complex with Nirmatrelvir==
<StructureSection load='8e26' size='340' side='right'caption='[[8e26]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8e26]] 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=8E26 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E26 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]] 1.845&#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>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=8e26 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e26 OCA], [https://pdbe.org/8e26 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e26 RCSB], [https://www.ebi.ac.uk/pdbsum/8e26 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e26 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (M(pro)) is an attractive target for antivirals. The clinically approved drug nirmatrelvir and the clinical candidate ensitrelvir have so far showed great potential for treatment of viral infection. However, the broad use of antivirals is often associated with resistance generation. Herein, we enzymatically characterized 14 naturally occurring M(pro) polymorphisms that are close to the binding site of these antivirals. Nirmatrelvir retained its potency against most polymorphisms tested, while mutants G143S and Q189K were associated with diminished inhibition constants. For ensitrelvir, diminished inhibition constants were observed for polymorphisms M49I, G143S, and R188S, but not for Q189K, suggesting a distinct resistance profile between inhibitors. In addition, the crystal structures of selected polymorphisms revealed interactions that were critical for loss of potency. In conclusion, our data will assist the monitoring of potential resistant strains, support the design of combined therapy, as well as assist the development of the next generation of M(pro) inhibitors.

Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease.,Noske GD, de Souza Silva E, de Godoy MO, Dolci I, Fernandes RS, Guido RVC, Sjo P, Oliva G, Godoy AS J Biol Chem. 2023 Mar;299(3):103004. doi: 10.1016/j.jbc.2023.103004. Epub 2023 , Feb 10. PMID:36775130<ref>PMID:36775130</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8e26" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Godoy AS]]
[[Category: Noske GD]]
[[Category: Oliva G]]