7LCQ

N-terminal finger stabilizes feline drug GC376 in coronavirus 3CL protease

7LCQ の概要

• エントリーDOI: 10.2210/pdb7lcq/pdb
• 分子名称: 3C-like proteinase, 1,2-ETHANEDIOL, N~2~-[(benzyloxy)carbonyl]-N-{(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-L-leucinamide, ... (4 entities in total)
• 機能のキーワード: covid-19, sars-cov-1, 3clpro, coronavirus, main protease, kinetics, sars, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Severe acute respiratory syndrome coronavirus (SARS-CoV)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34406.26

構造登録者

Khan, M.B.,Arutyunova, E.,Young, H.S.,Lemieux, M.J. (登録日: 2021-01-11, 公開日: 2021-05-12, 最終更新日: 2024-11-20)

主引用文献

Arutyunova, E.,Khan, M.B.,Fischer, C.,Lu, J.,Lamer, T.,Vuong, W.,van Belkum, M.J.,McKay, R.T.,Tyrrell, D.L.,Vederas, J.C.,Young, H.S.,Lemieux, M.J.
N-Terminal Finger Stabilizes the S1 Pocket for the Reversible Feline Drug GC376 in the SARS-CoV-2 M pro Dimer.
J.Mol.Biol., 433:167003-167003, 2021

PubMed Abstract: The main protease (M, also known as 3CL protease) of SARS-CoV-2 is a high priority drug target in the development of antivirals to combat COVID-19 infections. A feline coronavirus antiviral drug, GC376, has been shown to be effective in inhibiting the SARS-CoV-2 main protease and live virus growth. As this drug moves into clinical trials, further characterization of GC376 with the main protease of coronaviruses is required to gain insight into the drug's properties, such as reversibility and broad specificity. Reversibility is an important factor for therapeutic proteolytic inhibitors to prevent toxicity due to off-target effects. Here we demonstrate that GC376 has nanomolar K values with the M from both SARS-CoV-2 and SARS-CoV strains. Restoring enzymatic activity after inhibition by GC376 demonstrates reversible binding with both proteases. In addition, the stability and thermodynamic parameters of both proteases were studied to shed light on physical chemical properties of these viral enzymes, revealing higher stability for SARS-CoV-2 M. The comparison of a new X-ray crystal structure of M from SARS-CoV complexed with GC376 reveals similar molecular mechanism of inhibition compared to SARS-CoV-2 M, and gives insight into the broad specificity properties of this drug. In both structures, we observe domain swapping of the N-termini in the dimer of the M, which facilitates coordination of the drug's P1 position. These results validate that GC376 is a drug with an off-rate suitable for clinical trials.

PubMed: 33895266
DOI: 10.1016/j.jmb.2021.167003

実験手法

X-RAY DIFFRACTION (2.15 Å)