8RA0

Crystal structure of CysF

8RA0 の概要

• エントリーDOI: 10.2210/pdb8ra0/pdb
• 分子名称: AMP-dependent synthetase, TETRAETHYLENE GLYCOL, CITRATE ANION, ... (4 entities in total)
• 機能のキーワード: beta lactone formation, biosynthetic protein
• 由来する生物種: Kitasatospora cystarginea
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 54782.66

構造登録者

Levy, C.W. (登録日: 2023-11-30, 公開日: 2024-06-26, 最終更新日: 2024-10-09)

主引用文献

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

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: 38951647
DOI: 10.1038/s41589-024-01657-7

実験手法

X-RAY DIFFRACTION (1.89 Å)