8ig7 | pdb_00008ig7

Crystal structure of SARS-Cov-2 main protease G15S mutant in complex with GC376

spinqualitylabelsall models 8ig7, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ig7 is a 2 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 1.69Å Ligands: UED Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The main protease (M(pro)) of coronaviruses participates in viral replication, serving as a hot target for drug design. GC376 is able to effectively inhibit the activity of M(pro), which is due to nucleophilic addition of GC376 by binding covalently with Cys145 in M(pro) active site. Here, we used fluorescence resonance energy transfer (FRET) assay to analyze the IC(50) values of GC376 against M(pro)s from six different coronaviruses (SARS-CoV-2, HCoV-229E, HCoV-HUK1, MERS-CoV, SARS-CoV, HCoV-NL63) and five M(pro) mutants (G15S, M49I, K90R, P132H, S46F) from SARS-CoV-2 variants. The results showed that GC376 displays effective inhibition to various coronaviral M(pro)s and SARS-CoV-2 M(pro) mutants. In addition, the crystal structures of SARS-CoV-2 M(pro) (wide type)-GC376, SARS-CoV M(pro)-GC376, MERS-CoV M(pro)-GC376, and SARS-CoV-2 M(pro) mutants (G15S, M49I, S46F, K90R, and P132H)-GC376 complexes were solved. We found that GC376 is able to fit into the active site of M(pro)s from different coronaviruses and different SARS-CoV-2 variants properly. Detailed structural analysis revealed key molecular determinants necessary for inhibition and illustrated the binding patterns of GC376 to these different M(pro)s. In conclusion, we not only proved the inhibitory activity of GC376 against different M(pro)s including SARS-CoV-2 M(pro) mutants, but also revealed the molecular mechanism of inhibition by GC376, which will provide scientific guidance for the development of broad-spectrum drugs against SARS-CoV-2 as well as other coronaviruses. Structural Basis for Coronaviral Main Proteases Inhibition by the 3CLpro Inhibitor GC376.,Lin C, Zhu Z, Jiang H, Zou X, Zeng X, Wang J, Zeng P, Li W, Zhou X, Zhang J, Wang Q, Li J J Mol Biol. 2024 Mar 15;436(6):168474. doi: 10.1016/j.jmb.2024.168474. Epub 2024 , Feb 2. PMID:38311236 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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