8J3B

Crystal structure of SARS-Cov-2 main protease S46F mutant in complex with PF00835231

Summary for 8J3B

• Entry DOI: 10.2210/pdb8j3b/pdb
• Descriptor: 3C-like proteinase nsp5, N-[(2S)-1-({(2S,3S)-3,4-dihydroxy-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (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: 67366.95

Authors

Zhou, X.L.,Lin, C.,Zou, X.F.,Zhang, J.,Li, J. (deposition date: 2023-04-16, release date: 2024-04-17, Last modification date: 2025-05-07)

Primary citation

Zhou, X.,Lu, X.,Lin, C.,Zou, X.,Li, W.,Zeng, X.,Wang, J.,Zeng, P.,Wang, W.,Zhang, J.,Jiang, H.,Li, J.
Structural basis for the inhibition of coronaviral main proteases by PF-00835231.
Acta Biochim.Biophys.Sin., 56:1813-1822, 2024

PubMed Abstract: The main protease (M ) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M . Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M and seven M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M s. In addition, the crystal structures of SARS-CoV-2 M , SARS-CoV M , MERS-CoV M , and seven SARS-CoV-2 M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M s. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

PubMed: 39076076
DOI: 10.3724/abbs.2024122

Experimental method

X-RAY DIFFRACTION (1.64 Å)