6LNQ

The co-crystal structure of SARS-CoV 3C Like Protease with aldehyde inhibitor M7

Summary for 6LNQ

• Entry DOI: 10.2210/pdb6lnq/pdb
• Descriptor: Severe Acute Respiratory Syndrome Coronavirus 3c Like Protease, N-[(2S)-3-methyl-1-[[(2S)-4-methyl-1-oxidanylidene-1-[[(2S)-1-oxidanylidene-3-[(3S)-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]amino]-1-oxidanylidene-butan-2-yl]-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: coronavirus 3c, protease, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Severe acute respiratory syndrome-related coronavirus (SARSr-CoV)
• Total number of polymer chains: 1
• Total formula weight: 34388.25

Authors

Wang, H.,Shang, L.Q. (deposition date: 2020-01-01, release date: 2020-05-27, Last modification date: 2024-10-23)

Primary citation

Wang, H.,He, S.,Deng, W.,Zhang, Y.,Li, G.,Sun, J.,Zhao, W.,Guo, Y.,Yin, Z.,Li, D.,Shang, L.
Comprehensive Insights into the Catalytic Mechanism of Middle East Respiratory Syndrome 3C-Like Protease and Severe Acute Respiratory Syndrome 3C-Like Protease.
Acs Catalysis, 10:5871-5890, 2020

PubMed Abstract: Coronavirus 3C-like protease (3CL) is a highly conserved cysteine protease employing a catalytic dyad for its functions. 3CL is essential to the viral life cycle and, therefore, is an attractive target for developing antiviral agents. However, the detailed catalytic mechanism of coronavirus 3CL remains largely unknown. We took an integrated approach of employing X-ray crystallography, mutational studies, enzyme kinetics study, and inhibitors to gain insights into the mechanism. Such experimental work is supplemented by computational studies, including the prereaction state analysis, the ab initio calculation of the critical catalytic step, and the molecular dynamic simulation of the wild-type and mutant enzymes. Taken together, such studies allowed us to identify a residue pair (Glu-His) and a conserved His as critical for binding; a conserved GSCGS motif as important for the start of catalysis, a partial negative charge cluster (PNCC) formed by Arg-Tyr-Asp as essential for catalysis, and a conserved water molecule mediating the remote interaction between PNCC and catalytic dyad. The data collected and our insights into the detailed mechanism have allowed us to achieve a good understanding of the difference in catalytic efficiency between 3CL from SARS and MERS, conduct mutational studies to improve the catalytic activity by 8-fold, optimize existing inhibitors to improve the potency by 4-fold, and identify a potential allosteric site for inhibitor design. All such results reinforce each other to support the overall catalytic mechanism proposed herein.

PubMed: 32391184
DOI: 10.1021/acscatal.0c00110

Experimental method

X-RAY DIFFRACTION (2.244 Å)