8YKK
Crystal structure of SARS main protease in complex with X77
Summary for 8YKK
| Entry DOI | 10.2210/pdb8ykk/pdb |
| Descriptor | 3C-like proteinase nsp5, N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide (3 entities in total) |
| Functional Keywords | viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Severe acute respiratory syndrome-related coronavirus |
| Total number of polymer chains | 1 |
| Total formula weight | 33526.34 |
| Authors | |
| Primary citation | Jiang, H.,Li, W.,Zhou, X.,Zhang, J.,Li, J. Crystal structures of coronaviral main proteases in complex with the non-covalent inhibitor X77. Int.J.Biol.Macromol., 276:133706-133706, 2024 Cited by PubMed Abstract: Main proteases (Ms) are a class of conserved cysteine hydrolases among coronaviruses and play a crucial role in viral replication. Therefore, Ms are ideal targets for the development of pan-coronavirus drugs. X77, previously developed against SARS-CoV M, was repurposed as a non-covalent tight binder inhibitor against SARS-CoV-2 M during COVID-19 pandemic. Many novel inhibitors with favorable efficacy have been discovered using X77 as a reference, suggesting that X77 could be a valuable scaffold for drug design. However, the broad-spectrum performance of X77 and underlying mechanism remain less understood. Here, we reported the crystal structures of Ms from SARS-CoV-2, SARS-CoV, and MERS-CoV, and several M mutants from SARS-CoV-2 variants bound to X77. A detailed analysis of these structures revealed key structural determinants essential for interaction and elucidated the binding modes of X77 with different coronaviral Ms. The potencies of X77 against these investigated Ms were further evaluated through molecular dynamic simulation and binding free energy calculation. These data provide molecular insights into broad-spectrum inhibition against coronaviral Ms by X77 and the similarities and differences of X77 when bound to various Ms, which will promote X77-based design of novel antivirals with broad-spectrum efficacy against different coronaviruses and SARS-CoV-2 variants. PubMed: 38981557DOI: 10.1016/j.ijbiomac.2024.133706 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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