8fig

Room-temperature X-ray structure of SARS-CoV-2 main protease double mutant E290A/R298A in complex with GC373

spinqualitylabelsall models 8fig, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fig is a 1 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.75Å Ligands: UED Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed A critical step for SARS-CoV-2 assembly and maturation involves the autoactivation of the main protease (MPro(WT)) from precursor polyproteins. Upon expression, a model precursor of MPro(WT) mediates its own release at its termini rapidly to yield a mature dimer. A construct with an E290A mutation within MPro exhibits time dependent autoprocessing of the accumulated precursor at the N-terminal nsp4/nsp5 site followed by the C-terminal nsp5/nsp6 cleavage. In contrast, a precursor containing E290A and R298A mutations (MPro(M)) displays cleavage only at the nsp4/nsp5 site to yield an intermediate monomeric product, which is cleaved at the nsp5/nsp6 site only by MPro(WT). MPro(M) and the catalytic domain (MPro(1-199)) fused to the truncated nsp4 region also show time-dependent conversion in vitro to produce MPro(M) and MPro(1-199), respectively. The reactions follow first-order kinetics indicating that the nsp4/nsp5 cleavage occurs via an intramolecular mechanism. These results support a mechanism involving an N-terminal intramolecular cleavage leading to an increase in the dimer population and followed by an intermolecular cleavage at the C-terminus. Thus, targeting the predominantly monomeric MPro precursor for inhibition may lead to the identification of potent drugs for treatment. Insights into the mechanism of SARS-CoV-2 main protease autocatalytic maturation from model precursors.,Aniana A, Nashed NT, Ghirlando R, Coates L, Kneller DW, Kovalevsky A, Louis JM Commun Biol. 2023 Nov 13;6(1):1159. doi: 10.1038/s42003-023-05469-8. PMID:37957287 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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