View source for 7tdu


==Joint X-ray/neutron structure of SARS-CoV-2 main protease (3CL Mpro) in complex with BBH-1==
<StructureSection load='7tdu' size='340' side='right'caption='[[7tdu]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TDU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TDU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Hybrid , Neutron Diffraction , X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DOD:DEUTERATED+WATER'>DOD</scene>, <scene name='pdbligand=I1W:(1R,2S,5S)-N-{(1S,2S)-1-(1,3-benzothiazol-2-yl)-1-hydroxy-3-[(3S)-2-oxo(1-~2~H)pyrrolidin-3-yl]propan-2-yl}-3-{N-[tert-butyl(~2~H)carbamoyl]-3-methyl-L-(N-~2~H)valyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-(~2~H)carboxamide'>I1W</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=7tdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tdu OCA], [https://pdbe.org/7tdu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tdu RCSB], [https://www.ebi.ac.uk/pdbsum/7tdu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tdu ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
The COVID-19 pandemic continues to disrupt everyday life, with constantly emerging SARS-CoV-2 variants threatening to render current vaccines ineffective. Small-molecule antivirals can provide an important therapeutic treatment option that is subject to challenges caused by the virus variants. The viral main protease (M (pro) ) is critical for the virus replication and thus is considered an attractive drug target for specific protease inhibitors. We performed the design and characterization of three reversible covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2, whose structures were derived from those of hepatitis C protease inhibitors boceprevir and narlaprevir. A joint X-ray/neutron structure of the M (pro) /BBH-1 complex demonstrated that a Cys145 thiolate reaction with the inhibitoraeuros keto-warhead creates a negatively charged oxyanion, similar to that proposed for the M (pro) -catalyzed peptide bond hydrolysis. Protonation states of the ionizable residues in the M (pro) active site adapt to the inhibitor, which appears to be an intrinsic property of M (pro) . Structural comparisons of the hybrid inhibitors with PF-07321332 revealed unconventional interactions of PF-07321332 with M (pro) which may explain its more favorable enthalpy of binding and consequently higher potency. BBH-1, BBH-2 and NBH-2 demonstrated comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease: room-temperature X-ray and neutron crystallography, binding thermodynamics, and antiviral activity.,Kneller D, Li H, Phillips G, Weiss K, Zhang Q, Arnould M, Jonsson C, Surendranathan S, Parvathareddy J, Blakeley M, Coates L, Louis J, Bonnesen P, Kovalevsky A Res Sq. 2022 Feb 11. doi: 10.21203/rs.3.rs-1318037/v1. PMID:35169792<ref>PMID:35169792</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
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</StructureSection>
[[Category: Large Structures]]
[[Category: Coates L]]
[[Category: Kneller DW]]
[[Category: Kovalevsky A]]