7z4s

Crystal structure of SARS-CoV-2 Mpro in complex with cyclic peptide GM4 including unnatural amino acids.

spinqualitylabelsall models 7z4s, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7z4s is a 4 chain structure with sequence from Severe acute respiratory syndrome coronavirus 2 and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.7Å Ligands: ACE, CSO, DMS, DTY, EDO, II7, NH2, PEG, PGE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed gamma-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of gamma-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic gamma(2,4)-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M(pro)). Two kinds of cyclic gamma(2,4)-amino acids, cis-3-aminocyclobutane carboxylic acid (gamma(1)) and (1R,3S)-3-aminocyclopentane carboxylic acid (gamma(2)), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M(pro) inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with gamma(1) at the fourth position, manifests a 5.2 nM dissociation constant. An M(pro):GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The gamma(1) interacts with the S1' catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and M(pro) enabled production of a variant with a 5-fold increase in potency. In vitro selection of macrocyclic peptide inhibitors containing cyclic gamma(2,4)-amino acids targeting the SARS-CoV-2 main protease.,Miura T, Malla TR, Owen CD, Tumber A, Brewitz L, McDonough MA, Salah E, Terasaka N, Katoh T, Lukacik P, Strain-Damerell C, Mikolajek H, Walsh MA, Kawamura A, Schofield CJ, Suga H Nat Chem. 2023 Jul;15(7):998-1005. doi: 10.1038/s41557-023-01205-1. Epub 2023 May , 22. PMID:37217786 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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