8jpq

SARS-CoV-2 Mpro in complex with D-5-96

spinqualitylabelsall models 8jpq, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8jpq 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 2.7Å Ligands: ACY, ALA, ILE, V3E Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The main protease (M(pro) ) of SARS-CoV-2 is a well-characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4-S1' pocket of M(pro) ; however, it is still unclear whether the S1'-S3' pocket per se can serve as a new site for drug discovery. In this study, the S1'-S3' pocket of M(pro) was found to differentially recognize viral peptidyl substrates. For instance, S3' in M(pro) strongly favors Phe or Trp, and S1' favors Ala. The peptidyl inhibitor D-4-77, which possesses an alpha-bromoacetamide warhead, was discovered to be a promising inhibitor of M(pro) , with an IC(50) of 0.95 muM and an antiviral EC(50) of 0.49 muM. The M(pro) /inhibitor co-crystal structure confirmed the binding mode of the inhibitor to the S1'-S3' pocket and revealed a covalent mechanism. In addition, D-4-77 functions as an immune protectant and suppresses SARS-CoV-2 M(pro) -induced antagonism of the host NF-kappaB innate immune response. These findings indicate that the S1'-S3' pocket of SARS-CoV-2 M(pro) is druggable, and that inhibiting SARS-CoV-2 M(pro) can simultaneously protect human innate immunity and inhibit virion assembly. The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors.,Liu M, Li J, Liu W, Yang Y, Zhang M, Ye Y, Zhu W, Zhou C, Zhai H, Xu Z, Zhang G, Huang H Angew Chem Int Ed Engl. 2023 Oct 9;62(41):e202309657. doi: , 10.1002/anie.202309657. Epub 2023 Sep 4. PMID:37609788 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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