8HVX

Crystal structure of SARS-Cov-2 main protease Y54C mutant in complex with PF07304814

Summary for 8HVX

• Entry DOI: 10.2210/pdb8hvx/pdb
• Descriptor: 3C-like proteinase nsp5, [(3~{S})-3-[[(2~{S})-2-[(4-methoxy-1~{H}-indol-2-yl)carbonylamino]-4-methyl-pentanoyl]amino]-2-oxidanylidene-4-[(3~{R})-2-oxidanylidene-3,4-dihydropyrrol-3-yl]butyl] dihydrogen phosphate (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 67282.63

Authors

Zhou, X.L.,Zhang, J.,Li, J. (deposition date: 2022-12-28, release date: 2024-01-17, Last modification date: 2024-02-07)

Primary citation

Jiang, H.,Zou, X.,Zeng, P.,Zeng, X.,Zhou, X.,Wang, J.,Zhang, J.,Li, J.
Crystal structures of main protease (M pro ) mutants of SARS-CoV-2 variants bound to PF-07304814.
Mol Biomed, 4:23-23, 2023

PubMed Abstract: There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (M) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 M with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 M. However, the binding modes of PF-07304814 with Ms from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six M mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to M mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant Ms. Patterns for PF-07304814 to bind with these investigated M mutants and the wild-type M are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of M mutants when bound to an inhibitor.

PubMed: 37532968
DOI: 10.1186/s43556-023-00134-2

Experimental method

X-RAY DIFFRACTION (1.75 Å)