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TitleCrosslinking intermodular condensation in non-ribosomal peptide biosynthesis.
Journal, issue, pagesNature, Vol. 638, Issue 8049, Page 261-269, Year 2025
Publish dateDec 11, 2024
AuthorsGraham W Heberlig / James J La Clair / Michael D Burkart /
PubMed AbstractNon-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called ...Non-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called megasynthetases. They synthesize polypeptides using peptidyl carrier proteins that shuttle each amino acid through modular loading, modification and elongation steps, and remain challenging to structurally characterize, owing in part to the inherent dynamics of their multi-domain and multi-modular architectures. Here we have developed site-selective crosslinking probes to conformationally constrain and resolve the interactions between carrier proteins and their partner enzymatic domains. We apply tetrazine click chemistry to trap the condensation of two carrier protein substrates within the active site of the condensation domain that unites the first two modules of tyrocidine biosynthesis and report the high-resolution cryo-EM structure of this complex. Together with the X-ray crystal structure of the first carrier protein crosslinked to its epimerization domain, these structures highlight captured intermodular recognition events and define the processive movement of a carrier protein from one catalytic step to the next. Characterization of these structural relationships remains central to understanding the molecular details of these unique synthetases and critically informs future synthetic biology design of these pathways.
External linksNature / PubMed:39663458 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.18 - 3.31 Å
Structure data

44493

9bfd

EMDB-44493, PDB-9bfd:
Tyrocidine synthetase modules 1 and 2 crosslinked in the condensation state, complex A
Method: EM (single particle) / Resolution: 2.97 Å

44494

9bfe

EMDB-44494, PDB-9bfe:
Tyrocidine synthetase modules 1 and 2 crosslinked in the condensation state, complex B
Method: EM (single particle) / Resolution: 3.23 Å

44495

9bff

EMDB-44495, PDB-9bff:
Tyrocidine synthetase modules 1 and 2 crosslinked in the condensation state, complex C
Method: EM (single particle) / Resolution: 3.31 Å

PDB-9bfg:
Structure of the crosslinked PCP-E didomain of tyrocidine synthetase A
Method: X-RAY DIFFRACTION / Resolution: 2.18 Å

Chemicals

PDB-1an1:
LEECH-DERIVED TRYPTASE INHIBITOR/TRYPSIN COMPLEX

ChemComp-PR8:
5'-O-[(R)-hydroxy{[(2S)-pyrrolidin-2-ylcarbonyl]oxy}phosphoryl]adenosine

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM

PDB-1an7:
RIBOSOMAL PROTEIN S8 FROM THERMUS THERMOPHILUS

ChemComp-SO4:
SULFATE ION

ChemComp-MES:
2-(N-MORPHOLINO)-ETHANESULFONIC ACID / pH buffer*YM

ChemComp-GOL:
GLYCEROL

ChemComp-2GH:
N~3~-[(2R)-2-hydroxy-3,3-dimethyl-4-(phosphonooxy)butanoyl]-N-pentyl-beta-alaninamide

ChemComp-HOH:
WATER

Source
  • brevibacillus parabrevis (bacteria)
KeywordsISOMERASE / Complex / Crosslinked / NRPS / BIOSYNTHETIC PROTEIN

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