7Z4S
Crystal structure of SARS-CoV-2 Mpro in complex with cyclic peptide GM4 including unnatural amino acids.
Summary for 7Z4S
| Entry DOI | 10.2210/pdb7z4s/pdb |
| Descriptor | 3C-like proteinase nsp5, Macrocyclic peptide inhibitor, DI(HYDROXYETHYL)ETHER, ... (7 entities in total) |
| Functional Keywords | protease, unknown function |
| Biological source | Severe acute respiratory syndrome coronavirus 2 More |
| Total number of polymer chains | 4 |
| Total formula weight | 71373.41 |
| Authors | Owen, C.D.,Miura, T.,Malla, T.,Lukacik, L.,Strain-Damerell, C.M.,Tumber, A.,Brewitz, L.,McDonough, M.A.,Salah, E.,Terasaka, N.,Katoh, T.,Kawamura, A.,Schofield, C.J.,Suga, H.,Walsh, M.A. (deposition date: 2022-03-04, release date: 2023-03-22, Last modification date: 2024-10-16) |
| Primary citation | Miura, T.,Malla, T.R.,Owen, C.D.,Tumber, A.,Brewitz, L.,McDonough, M.A.,Salah, E.,Terasaka, N.,Katoh, T.,Lukacik, P.,Strain-Damerell, C.,Mikolajek, H.,Walsh, M.A.,Kawamura, A.,Schofield, C.J.,Suga, H. In vitro selection of macrocyclic peptide inhibitors containing cyclic gamma 2,4 -amino acids targeting the SARS-CoV-2 main protease. Nat.Chem., 15:998-1005, 2023 Cited by PubMed Abstract: γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M). Two kinds of cyclic γ-amino acids, cis-3-aminocyclobutane carboxylic acid (γ) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ at the fourth position, manifests a 5.2 nM dissociation constant. An M:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ 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 enabled production of a variant with a 5-fold increase in potency. PubMed: 37217786DOI: 10.1038/s41557-023-01205-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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