9M6R

Crystal structure of SARS-Cov-2 main protease E166N mutant in complex with Pomotrelvir

Summary for 9M6R

• Entry DOI: 10.2210/pdb9m6r/pdb
• Descriptor: 3C-like proteinase nsp5, Pomotrelvir bound form (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67183.55

Authors

Li, W.W.,Zhang, J.,Li, J. (deposition date: 2025-03-07, release date: 2026-01-14, Last modification date: 2026-01-21)

Primary citation

Zhou, X.,Guo, L.,Li, W.,Zeng, P.,Li, J.
Structural basis and inhibitory mechanism of the interaction between pomotrelvir and SARS-CoV-2 main protease mutants.
Int.J.Biol.Macromol., 339:149954-149954, 2025

PubMed Abstract: Although the SARS-CoV-2 pandemic has passed, the continuous emergence of variants and the repeated occurrence of coronaviral pandemics in the past make the development of broad-spectrum anti-coronavirus drugs crucial. M is an ideal target for the treatment of coronavirus. Pomotrelvir is a novel M inhibitor that has completed phase II clinical trials. This study systematically evaluated the inhibitory efficacy and binding mechanism of Pomotrelvir against SARS-CoV-2 M and six mutants (E166R, E166N, H163A, S46F, M49I, V186F) through enzymatic experiments, crystal structure analysis, and molecular dynamics simulations. The results indicated that the inhibitory activity of Pomotrelvir against the mutants was significantly reduced compared to the wild type (116 to 208 times), but still retained micromolar-level inhibitory capacity. In detail, E166R, E166N, H163A, S46F, M49I, and V186F result in reduced binding affinity and inhibitory effects of Pomotrelvir due to the disruption of hydrogen bonds, changes in binding conformation, and reduced stability of the complex conformation. An interesting discovery is that Pomotrelvir is exclusively present in the protomer B of the H163A mutant, where the binding pocket exhibits significant expansion and enhanced negative charge. This study reveals the structural basis by which Pomotrelvir maintains its inhibitory activity against M mutants through covalent inhibition mechanisms and dynamic interaction networks, providing an important theoretical basis for optimizing the design of broad-spectrum antiviral drugs against coronaviruses and addressing drug resistance mutations.

PubMed: 41482225
DOI: 10.1016/j.ijbiomac.2025.149954

Experimental method

X-RAY DIFFRACTION (1.94 Å)