Work

Extending the Peptide/Protein Interaction Paradigm to a Protein/Protein Engagement Model in RiPP Biosynthesis

Year: 2025

Type: article

Abstract: Enzymatic post-translational modification of small precursor peptides generates a wide diversity of bioactive peptidic natural products. The interaction between the precursor peptide and the peptide modifying enzyme relies on recognition of the N-terminal region of the precursor peptide─termed the leader peptide─by the modifying enzyme. In this study, we describe a model for the recognition of atypically long and highly structured nitrile hydratase-like leader peptides (NHLPs) by an azoline forming YcaO cyclodehydratase. Predicated upon the unique structure of NHLPs, the binding model relies on protein/protein interactions between higher-order secondary and tertiary structures of the NHLP and the modifying enzyme. In light of previous findings, we report that different modifying enzymes bind to different molecular surfaces of the NHLPs. These findings illustrate the modularity of different NHLP structural features and how fine-tuning of intermolecular interactions is necessary for efficient catalysis.

Source: ACS Chemical Biology

DOI: 10.1021/acschembio.5c00411

Authors: Mujeeb A. Wakeel, Elizabeth A. Corbin, Andrew C. McShan, Vinayak Agarwal

Institution: Georgia Institute of Technology

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

Open Access status: hybrid

Estimated APC paid: $4,500

Funders: Georgia Institute of Technology, National Institutes of Health, National Institute of General Medical Sciences