Journal Article

PUBDB-2025-04107

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural Basis for a Scaffolding Role of the COM Domain in Nonribosomal Peptide Synthetases

Diecker, J. ; Hermanns, B. ; Rüschenbaum, J. ; Rasche, R. ; Dörner, W. ; Schröder, A. ; Kuemmel, D.Extern*EMBL* ; Mootz, H. D. (Corresponding author)

2025
Wiley-VCH Weinheim

This record in other databases:  

Please use a persistent id in citations: doi:10.1002/anie.202506621

Abstract: Nonribosomal peptide synthetases (NRPSs) are multi-domain enzymes that catalyze the biosynthesis of therapeutically relevant natural products. Efficient peptide synthesis relies on intricate domain interactions, whose underlying principles remain poorly understood. The communication-mediating (COM) domains facilitate interactions between separate NRPS subunits. For unknown reasons, COM domains co-occur with epimerization (E) domains, are partially embedded within the adjacent condensation (C) domains and can also be found as internal cis-COM domains. These features set COM domains apart from other docking domains. We present the first crystal structure of a cis-COM domain within an E-COM-C domain arrangement from modules 4 and 5 of bacitracin synthetase 3 (BacC). The structure reveals a compactly folded COM domain sandwiched between E and C domains, suggesting a role of the COM domain in orienting these domains for efficient peptidyl carrier protein (PCP) shuttling. Through mutational analyses, dipeptide formation assays, and proximity-dependent photo-crosslinking experiments, we investigated both cis- and trans-COM domains and provide evidence supporting a principal role of COM domains as scaffolds of NRPS architecture. Their function as docking domains may be a secondary consequence of their division into separate donor and acceptor parts.

---

Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)

---

Database coverage:
; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---