A new inactive conformation of SARS-CoV-2 main protease
Emanuele Fornasier, Maria Ludovica Macchia, Gabriele Giachin, Alice Sosic,
Matteo Pavan, Mattia Sturlese, Cristiano Salata, Stefano Moro, Barbara Gatto,
Massimo Bellanda and Roberto Battistutta [1]
Molecular Tour
The SARS-CoV-2 main protease, Mpro or 3CLpro, is a cysteine peptidase involved in the processing of the two overlapping polyproteins pp1a and pp1ab, with the formation of individual mature non-structural proteins (nsp). Playing a pivotal role in genome replication and transcription, it is a validated antiviral drug target against Covid-19 pandemic. Mpro forms homo-dimers, the only enzymatically active form of the enzyme. Each Mpro protomer is composed of three structural domains; the chymotrypsin- and 3C protease-like domains I and II directly control the catalytic event. The substrate-binding site is between domains I and II, and, at variance with the classical catalytic triad of chymotrypsin-like proteases, SARS-CoV-2 Mpro has a catalytic dyad, consisting of His41 and Cys145. A structural element essential for the catalysis is the so-called “oxyanion loop”, comprising residues 138-145.
In this paper, we describe a new inactive structure of the main protease of SARS-CoV-2. Movements in the substrate-binding region and near the catalytic site result in a significant reshaping of the reaction center. Consequently, the conformation adopted by residues 139-144 of the oxyanion loop is catalytically-incompetent. Phe140, Leu141 and Asn142 play a major role in the shift between the new inactive and active conformations. The movements of the oxyanion loop and of the N- and C-termini result in the weakening of the dimeric architecture, as evidenced by the decreases in the interaction surface area and in the number of inter-protomer interactions. This novel conformation is relevant both for the comprehension of the mechanism of action of Mpro within the catalytic cycle and for the success of the structure-based drug design of anti-viral drugs.
References
- ↑ Fornasier E, Macchia ML, Giachin G, Sosic A, Pavan M, Sturlese M, Salata C, Moro S, Gatto B, Bellanda M, Battistutta R. A new inactive conformation of SARS-CoV-2 main protease. Acta Crystallogr D Struct Biol. 2022 Mar 1;78(Pt 3):363-378. doi:, 10.1107/S2059798322000948. Epub 2022 Feb 21. PMID:35234150 doi:http://dx.doi.org/10.1107/S2059798322000948
