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Structures and functions of nonribosomal peptide synthetases, natural antibiotic factories
Author(s) -
Schmeing Martin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.257.3
Subject(s) - adenylylation , nonribosomal peptide , gramicidin s , domain (mathematical analysis) , formylation , chemistry , stereochemistry , computational biology , combinatorial chemistry , biology , gramicidin , biosynthesis , biochemistry , enzyme , mathematics , mathematical analysis , membrane , catalysis
Nonribosomal peptide synthetases (NRPSs) are true macromolecular machines, using modular assembly‐line logic, a complex catalytic cycle, moving parts and many active sites to make their bio‐active products. We have determined a series of crystal structures of the initiation module of an antibiotic‐producing NRPS, linear gramicidin synthetase. This module includes the specialized tailoring formylation domain, and we capture states that represent every major step of the assembly‐line synthesis in the initiation module. The structures show how the formylation domain is incorporated into the NRPS architecture and how it has evolved to act in concert with the other domains in the synthetic cycle. The transitions between the sequential conformations in the cycle are very large, with both the peptidyl carrier protein and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlight the great versatility of NRPSs, as small domains repurpose and recycle their limited interfaces to interact with their various binding partners. Together our published and unpublished work presents a holistic view of the function of this elegant NRPS initiation module.Synthetic cycle (top) and structure (bottom) of the first module of the NRPS linear gramicidin synthetase