7XRS

Crystal structure of SARS-Cov-2 main protease in complex with inhibitor YH-53

Summary for 7XRS

• Entry DOI: 10.2210/pdb7xrs/pdb
• Descriptor: Replicase polyprotein 1a, N-[(2S)-1-[[(2S)-1-(1,3-benzothiazol-2-yl)-1-oxidanylidene-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]-4-methoxy-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 67449.02

Authors

Zhou, X.L.,Zhong, F.L.,Lin, C.,Zeng, P.,Zhang, J.,Li, J. (deposition date: 2022-05-11, release date: 2022-12-21, Last modification date: 2023-11-29)

Primary citation

Hu, X.,Lin, C.,Xu, Q.,Zhou, X.,Zeng, P.,McCormick, P.J.,Jiang, H.,Li, J.,Zhang, J.
Structural Basis for the Inhibition of Coronaviral Main Proteases by a Benzothiazole-Based Inhibitor.
Viruses, 14:-, 2022

PubMed Abstract: The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (M) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Ms. Crystal structures of Ms from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Ms from other coronaviruses. In consideration of the important role of M in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral M inhibitors that are safer and more effective.

PubMed: 36146880
DOI: 10.3390/v14092075

Experimental method

X-RAY DIFFRACTION (1.93 Å)