8YKO

Crystal structure of SARS-Cov-2 main protease P132H mutant in complex withX77

8YKO の概要

• エントリーDOI: 10.2210/pdb8yko/pdb
• 分子名称: 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)
• 機能のキーワード: viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67124.74

構造登録者

Li, W.W.,Zhang, J.,Li, J. (登録日: 2024-03-05, 公開日: 2024-11-27)

主引用文献

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

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: 38981557
DOI: 10.1016/j.ijbiomac.2024.133706

実験手法

X-RAY DIFFRACTION (2.11 Å)