A new inactive conformation of SARS-CoV-2 main protease.

Autor: Fornasier E; Department of Chemical Sciences, University of Padua, Via F. Marzolo 1, 35131 Padova, Italy., Macchia ML; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Giachin G; Department of Chemical Sciences, University of Padua, Via F. Marzolo 1, 35131 Padova, Italy., Sosic A; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Pavan M; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Sturlese M; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Salata C; Department of Molecular Medicine, University of Padua, Via Gabelli 63, 35121 Padova, Italy., Moro S; Molecular Modeling Section, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Gatto B; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Via F. Marzolo 5, 35131 Padova, Italy., Bellanda M; Department of Chemical Sciences, University of Padua, Via F. Marzolo 1, 35131 Padova, Italy., Battistutta R; Department of Chemical Sciences, University of Padua, Via F. Marzolo 1, 35131 Padova, Italy.
Jazyk: angličtina
Zdroj: Acta crystallographica. Section D, Structural biology [Acta Crystallogr D Struct Biol] 2022 Mar 01; Vol. 78 (Pt 3), pp. 363-378. Date of Electronic Publication: 2022 Feb 21.
DOI: 10.1107/S2059798322000948
Abstrakt: The SARS-CoV-2 main protease (M pro ) has a pivotal role in mediating viral genome replication and transcription of the coronavirus, making it a promising target for drugs against the COVID-19 pandemic. Here, a crystal structure is presented in which M pro adopts an inactive state that has never been observed before, called new-inactive. It is shown that the oxyanion loop, which is involved in substrate recognition and enzymatic activity, adopts a new catalytically incompetent conformation and that many of the key interactions of the active conformation of the enzyme around the active site are lost. Solvation/desolvation energetic contributions play an important role in the transition from the inactive to the active state, with Phe140 moving from an exposed to a buried environment and Asn142 moving from a buried environment to an exposed environment. In new-inactive M pro a new cavity is present near the S2' subsite, and the N-terminal and C-terminal tails, as well as the dimeric interface, are perturbed, with partial destabilization of the dimeric assembly. This novel conformation is relevant both for comprehension of the mechanism of action of M pro within the catalytic cycle and for the successful structure-based drug design of antiviral drugs.
(open access.)
Databáze: MEDLINE
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