View source for 7rw1


==Structure of the SARS-CoV-2 main protease in complex with inhibitor MPI28==
<StructureSection load='7rw1' size='340' side='right'caption='[[7rw1]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7rw1]] 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=7RW1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RW1 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=800:~{N}-[(2~{S})-3-methyl-1-[[(2~{S})-4-methyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]amino]-1-oxidanylidene-butan-2-yl]-1~{H}-indole-2-carboxamide'>800</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=7rw1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rw1 OCA], [https://pdbe.org/7rw1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rw1 RCSB], [https://www.ebi.ac.uk/pdbsum/7rw1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rw1 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
As an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (M(Pro)) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl M(Pro) inhibitors that contained also an aldehyde warhead and beta-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray crystal structures of their complexes with M(Pro), their inhibition of M(Pro) transiently expressed in 293T cells, and cellular toxicity and SARS-CoV-2 antiviral potency of selected inhibitors. These inhibitors have a large variation of determined in vitro enzymatic inhibition IC(50) values that range from 4.8 to 650 nM. The determined in vitro enzymatic inhibition IC(50) values reveal that relatively small side chains at both P2 and P3 positions are favorable for achieving high in vitro M(Pro) inhibition potency, the P3 position is tolerable toward unnatural amino acids with two alkyl substituents on the alpha-carbon, and the inhibition potency is sensitive toward the N-terminal protection group. X-ray crystal structures of M(Pro) bound with 16 inhibitors were determined. In all structures, the M(Pro) active site cysteine interacts covalently with the aldehyde warhead of the bound inhibitor to form a hemithioacetal that takes an S configuration. For all inhibitors, election density around the N-terminal protection group is weak indicating possible flexible binding of this group to M(Pro). In M(Pro), large structural variations were observed on residues N142 and Q189. Unlike their high in vitro enzymatic inhibition potency, most inhibitors showed low potency to inhibit M(Pro) that was transiently expressed in 293T cells. Inhibitors that showed high potency to inhibit M(Pro) transiently expressed in 293T cells all contain O-tert-butyl-threonine at the P3 position. These inhibitors also exhibited relatively low cytotoxicity and high antiviral potency. Overall, our current and previous studies indicate that O-tert-butyl-threonine at the P3 site is a key component to achieve high cellular and antiviral potency for tripeptidyl aldehyde inhibitors of M(Pro).

A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals.,Ma Y, Yang KS, Geng ZZ, Alugubelli YR, Shaabani N, Vatansever EC, Ma XR, Cho CC, Khatua K, Xiao J, Blankenship LR, Yu G, Sankaran B, Li P, Allen R, Ji H, Xu S, Liu WR Eur J Med Chem. 2022 Oct 5;240:114570. doi: 10.1016/j.ejmech.2022.114570. Epub , 2022 Jun 27. PMID:35779291<ref>PMID:35779291</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 7rw1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Liu W]]
[[Category: Sankaran B]]
[[Category: Yang K]]