9CJX

Solution NMR structure of the RiPP proteusin DprE2 from Desulfotomaculum sp.

Summary for 9CJX

• Entry DOI: 10.2210/pdb9cjx/pdb
• Descriptor: NHLP leader peptide family natural product (1 entity in total)
• Functional Keywords: proteusin, ripp, leader peptide, biosynthetic protein
• Biological source: Desulfotomaculum sp.
• Total number of polymer chains: 1
• Total formula weight: 11447.86

Authors

McShan, A.C.,Agarwal, V.,Vidya, F.N.U. (deposition date: 2024-07-08, release date: 2024-12-04, Last modification date: 2025-12-17)

Primary citation

Vidya, F.,Luo, Y.,Wu, H.,van der Donk, W.A.,McShan, A.C.,Agarwal, V.
Large protein-like leader peptides engage differently with RiPP halogenases and lanthionine synthetases.
Nat Commun, 16:9273-9273, 2025

PubMed Abstract: The biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs) involves binding of the N-terminal leader region of precursor peptides to peptide-modifying enzymes and subsequent modification of the C-terminal core. Canonical RiPP leaders are short and unstructured. However, atypical RiPP leaders called nitrile hydratase-like leader peptides (NHLPs) are longer and structured. The sequence and structural divergence dictate that the NHLPs engage with peptide modifying enzymes using binding modes that are distinct from that for the canonical short leader peptides. Here, we investigate the molecular basis of NHLP engagement with class II lanthionine synthetases (LanMs). Using genome mining, we identify a LanM that is selective for the NHLP while modifying diverse core peptides. The solution NMR structure of the NHLP reveals a rigid tertiary fold. Biochemically verified computational models support a bimodal mechanism for NHLP binding to LanMs. Findings developed here illuminate unique protein-protein interaction modalities that guide RiPP biosynthesis.

PubMed: 41115907
DOI: 10.1038/s41467-025-64365-3

Experimental method

SOLUTION NMR