8Z0S

Cryo-EM structure of trimer HtmB2-CT

8Z0S の概要

• エントリーDOI: 10.2210/pdb8z0s/pdb
• EMDBエントリー: 39714
• 分子名称: special condensation domain in NRPS (1 entity in total)
• 機能のキーワード: dimer of special condensation domain of nrps, biosynthetic protein
• 由来する生物種: Streptomyces
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 185467.89

構造登録者

Sun, Y.H.,Zhang, Z.Y.,Mei, Q. (登録日: 2024-04-10, 公開日: 2025-03-19, 最終更新日: 2025-06-18)

主引用文献

Mei, Q.,Wu, S.,Luo, M.,Ji, S.,Guo, J.,Dong, C.,Sun, G.,Wang, J.,Deng, Z.,Zhao, Y.L.,Zhang, Z.,Sun, Y.
Formation of the Diketopiperazine Moiety by a Distinct Condensation-Like Domain in Hangtaimycin Biosynthesis.
Angew.Chem.Int.Ed.Engl., 64:e202421950-e202421950, 2025

PubMed Abstract: Non-ribosomal peptide synthetases (NRPSs) are key enzymes in pharmaceutical synthesis, with condensation (C) domains catalyzing amide bond formation between aminoacyl substrates. However, recent research has elucidated that the catalytic capabilities of C domains extend beyond the traditional formation of peptide bonds. In this study, we elucidate the cyclization mechanism of the NRPS-derived natural products hangtaimycin (HTM), characterized by the formation of a 2,5-diketopiperazine (DKP) moiety which involves an intramolecular vinylamide-mediated nucleophilic attack instead of an N-terminal amino group. This cyclization is catalyzed by a terminal condensation-like (C) domain within the NRPS enzyme HtmB2. We investigated the evolutionary specificity of the HtmB2-C within Streptomyces spectabilis CCTCC M2017417. Employing a multidisciplinary analytical approach, we have delineated the molecular underpinnings of DKP formation within the HTM biosynthesis. This process is facilitated by residue R2776, which modulates the formation of reactive species and stabilizes the amidate through electrostatic interactions. Besides, we found a positive correlation between the alkaline strength of the residue at position 2776 and the activity of HtmB2-C. Our study elucidates the formation mechanism of DKPs in NRPS-derived natural products, thereby bridging a critical gap in the structural and mechanistic understanding of this field.

PubMed: 40000413
DOI: 10.1002/anie.202421950

実験手法

ELECTRON MICROSCOPY (2.61 Å)