ArticleBiophysical journal2010
Mutation of Glu-166 blocks the substrate-induced dimerization of SARS coronavirus main protease.
Article in Biophysical journal, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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89 citing papers in PubMed, 152 citations in OpenAlex.
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- An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations.Science translational medicine · 2024Article
- On Inactivation of the Coronavirus Main Protease.Journal of chemical information and modeling · 2024Article
- Finding potential inhibitors for Main protease (Mpro) of SARS-CoV-2 through virtual screening and MD simulation studies.Saudi journal of biological sciences · 2023Article
- Insights into the mechanism of SARS-CoV-2 main protease autocatalytic maturation from model precursors.Communications biology · 2023Article
- Bayesian Inference Elucidates the Catalytic Competency of the SARS-CoV-2 Main Protease 3CLAnalytical chemistry · 2023Article
- Systematic Analyses of the Resistance Potential of Drugs Targeting SARS-CoV-2 Main Protease.ACS infectious diseases · 2023Article
29 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The maturation of SARS coronavirus involves the autocleavage of polyproteins 1a and 1ab by the main protease (Mpro) and a papain-like protease; these represent attractive targets for the development of anti-SARS drugs. The functional unit of Mpro is a homodimer, and each subunit has a His-41cdots, three dots, centeredCys-145 catalytic dyad. Current thinking in this area is that Mpro dimerization is essential for catalysis, although the influence of the substrate binding on the dimer formation has never been explored. Here, we delineate the contributions of the peptide substrate to Mpro dimerization. Enzyme kinetic assays indicate that the monomeric mutant R298A/L exhibits lower activity but in a cooperative manner. Analytical ultracentrifugation analyses indicate that in the presence of substrates, the major species of R298A/L shows a significant size shift toward the dimeric form and the monomer-dimer dissociation constant of R298A/L decreases by 12- to 17-fold, approaching that for wild-type. Furthermore, this substrate-induced dimerization was found to be reversible after substrates were removed. Based on the crystal structures, a key residue, Glu-166, which is responsible for recognizing the Gln-P1 of the substrate and binding to Ser-1 of another protomer, will interact with Asn-142 and block the S1 subsite entrance in the monomer. Our studies indicate that mutation of Glu-166 in the R298A mutant indeed blocks the substrate-induced dimerization. This demonstrates that Glu-166 plays a pivotal role in connecting the substrate binding site with the dimer interface. We conclude that protein-ligand and protein-protein interactions are closely correlated in Mpro.
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