9RDE

Crystal structure of the B. licheniformis bacitacin sythetase 3 cis-E-COM-C domains

Summary for 9RDE

• Entry DOI: 10.2210/pdb9rde/pdb
• Descriptor: Bacitracin synthase 3 (1 entity in total)
• Functional Keywords: nonribosomal peptide synthetase, nrps, com domain, peptide binding protein
• Biological source: Bacillus licheniformis
• Total number of polymer chains: 1
• Total formula weight: 107455.18

Authors

Rasche, R.,Diecker, J.,Rueschenbaum, J.,Mootz, H.D.,Kuemmel, D. (deposition date: 2025-06-02, release date: 2025-08-06, Last modification date: 2025-09-17)

Primary citation

Diecker, J.,Hermanns, B.,Ruschenbaum, J.,Rasche, R.,Dorner, W.,Schroder, A.,Kummel, D.,Mootz, H.D.
Structural Basis for a Scaffolding Role of the COM Domain in Nonribosomal Peptide Synthetases.
Angew.Chem.Int.Ed.Engl., 64:e202506621-e202506621, 2025

PubMed 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.

PubMed: 40627840
DOI: 10.1002/anie.202506621

Experimental method

X-RAY DIFFRACTION (3.29 Å)