8RA0
Crystal structure of CysF
Summary for 8RA0
| Entry DOI | 10.2210/pdb8ra0/pdb |
| Descriptor | AMP-dependent synthetase, TETRAETHYLENE GLYCOL, CITRATE ANION, ... (4 entities in total) |
| Functional Keywords | beta lactone formation, biosynthetic protein |
| Biological source | Kitasatospora cystarginea |
| Total number of polymer chains | 1 |
| Total formula weight | 54782.66 |
| Authors | Levy, C.W. (deposition date: 2023-11-30, release date: 2024-06-26, Last modification date: 2024-10-09) |
| Primary citation | Xu, G.,Torri, D.,Cuesta-Hoyos, S.,Panda, D.,Yates, L.R.L.,Zallot, R.,Bian, K.,Jia, D.,Iorgu, A.I.,Levy, C.,Shepherd, S.A.,Micklefield, J. Cryptic enzymatic assembly of peptides armed with beta-lactone warheads. Nat.Chem.Biol., 20:1371-1379, 2024 Cited by PubMed Abstract: Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with β-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding β-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the β-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to β-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides. PubMed: 38951647DOI: 10.1038/s41589-024-01657-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
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