7XB4

Crystal structure of SARS-Cov-2 main protease D48N mutant in complex with PF07321332

Summary for 7XB4

• Entry DOI: 10.2210/pdb7xb4/pdb
• Descriptor: Replicase polyprotein 1a, (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 68652.21

Authors

Hu, X.H.,Li, J.,Zhang, J. (deposition date: 2022-03-20, release date: 2023-03-22, Last modification date: 2024-10-02)

Primary citation

Zhao, Z.,Zhu, Q.,Zhou, X.,Li, W.,Yin, X.,Li, J.
Structural Basis for the Inhibition of SARS-CoV-2 M pro D48N Mutant by Shikonin and PF-07321332.
Viruses, 16:-, 2023

PubMed Abstract: Preventing the spread of SARS-CoV-2 and its variants is crucial in the fight against COVID-19. Inhibition of the main protease (M) of SARS-CoV-2 is the key to disrupting viral replication, making M a promising target for therapy. PF-07321332 and shikonin have been identified as effective broad-spectrum inhibitors of SARS-CoV-2 M. The crystal structures of SARS-CoV-2 M bound to PF-07321332 and shikonin have been resolved in previous studies. However, the exact mechanism regarding how SARS-CoV-2 M mutants impact their binding modes largely remains to be investigated. In this study, we expressed a SARS-CoV-2 M mutant, carrying the D48N substitution, representing a class of mutations located near the active sites of M. The crystal structures of M D48N in complex with PF-07321332 and shikonin were solved. A detailed analysis of the interactions between M D48N and two inhibitors provides key insights into the binding pattern and its structural determinants. Further, the binding patterns of the two inhibitors to M D48N mutant and wild-type M were compared in detail. This study illustrates the possible conformational changes when the M D48N mutant is bound to inhibitors. Structural insights derived from this study will inform the development of new drugs against novel coronaviruses.

PubMed: 38257765
DOI: 10.3390/v16010065

Experimental method

X-RAY DIFFRACTION (2.07 Å)