Journal:Acta Cryst D:S2059798322000948
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<b>Molecular Tour</b><br> | <b>Molecular Tour</b><br> | ||
| - | The SARS-CoV-2 main protease, M<sup>pro</sup> or 3CL<sup>pro</sup>, 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. M<sup>pro</sup> forms <scene name='90/902772/Cv/10'>homo-dimers</scene>, the only enzymatically active form of the enzyme. <scene name='90/902772/Cv/14'>Dimeric assembly of the protease with the main structural features discussed in the text highlighted</scene>. Protomer A in blue-based colors, protomer B in yellow/red-based colors. In green the two oxyanion loops and the two catalytic cysteines 145. Each M<sup>pro</sup> 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 M<sup>pro</sup> 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. | + | The SARS-CoV-2 main protease, M<sup>pro</sup> or 3CL<sup>pro</sup>, 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. M<sup>pro</sup> forms <scene name='90/902772/Cv/10'>homo-dimers</scene>, the only enzymatically active form of the enzyme. <scene name='90/902772/Cv/14'>Dimeric assembly of the protease with the main structural features discussed in the text highlighted</scene> (PDB entry [[6y2e]]). Protomer A in blue-based colors, protomer B in yellow/red-based colors. In green the two oxyanion loops and the two catalytic cysteines 145. Each M<sup>pro</sup> protomer is composed of <scene name='90/902772/Cv/15'>three structural domains</scene>; 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 M<sup>pro</sup> 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 M<sup>pro</sup> within the catalytic cycle and for the success of the structure-based drug design of anti-viral drugs. | 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 M<sup>pro</sup> within the catalytic cycle and for the success of the structure-based drug design of anti-viral drugs. | ||
Revision as of 15:49, 2 February 2022
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