7TEH

Room temperature X-ray structure of SARS-CoV-2 main protease (3CL Mpro) in complex with BBH-2

7TEH の概要

• エントリーDOI: 10.2210/pdb7teh/pdb
• 関連するPDBエントリー: 7SI9
• 分子名称: 3C-like proteinase, (1R,2S,5S)-3-[N-(tert-butylcarbamoyl)-3-methyl-L-valyl]-N-{(1Z,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (3 entities in total)
• 機能のキーワード: sars-cov-2 main protease, homodimer, cysteine protease, covalent inhibitor, hydrolase, hydrolase-inhibitor complex, 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: 34330.21

構造登録者

Kovalevsky, A.,Kneller, D.W.,Coates, L. (登録日: 2022-01-05, 公開日: 2022-03-02, 最終更新日: 2024-10-23)

主引用文献

Kneller, D.W.,Li, H.,Phillips, G.,Weiss, K.L.,Zhang, Q.,Arnould, M.A.,Jonsson, C.B.,Surendranathan, S.,Parvathareddy, J.,Blakeley, M.P.,Coates, L.,Louis, J.M.,Bonnesen, P.V.,Kovalevsky, A.
Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease
Nat Commun, 13:2268-, 2022

PubMed Abstract: Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (M) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the M/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor's keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the M active site adapt to the inhibitor, which appears to be an intrinsic property of M. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with M which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

PubMed: 35477935
DOI: 10.1038/s41467-022-29915-z

実験手法

X-RAY DIFFRACTION (1.8 Å)