7LB7

Joint X-ray/neutron structure of SARS-CoV-2 main protease (3CL Mpro) in complex with Telaprevir

7LB7 の概要

• エントリーDOI: 10.2210/pdb7lb7/pdb
• 分子名称: 3C-like proteinase, (1S,3aR,6aS)-2-[(2S)-2-({(2S)-2-cyclohexyl-2-[(pyrazin-2-ylcarbonyl)amino]acetyl}amino)-3,3-dimethylbutanoyl]-N-[(2R,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl]octahydrocyclopenta[c]pyrrole-1-carboxamide (3 entities in total)
• 機能のキーワード: cysteine protease, dimer, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV,SARS-CoV-2)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34507.41

構造登録者

Kovalevsky, A.Y.,Kneller, D.W.,Coates, L. (登録日: 2021-01-07, 公開日: 2021-01-20, 最終更新日: 2024-11-13)

主引用文献

Kneller, D.W.,Phillips, G.,Weiss, K.L.,Zhang, Q.,Coates, L.,Kovalevsky, A.
Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography.
J.Med.Chem., 64:4991-5000, 2021

PubMed Abstract: The main protease (3CL M) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 M. To aid rational drug design, we determined a neutron structure of M in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free M, revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the M active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 M.

PubMed: 33755450
DOI: 10.1021/acs.jmedchem.1c00058

実験手法

NEUTRON DIFFRACTION (2.4 Å)
X-RAY DIFFRACTION (2 Å)