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Conformational remodeling enhances activity of lanthipeptide zinc-metallopeptidases.

Zhao C, Sheng W, Wang Y, Zheng J, Xie X, Liang Y, Wei W, Bao R, Wang H
Nat Chem Biol 18 724-732 (2022)
Related entries: 7v9n, 7v9p, 7v9q

Cited: 3 times
EuropePMC logo PMID: 35513512

Abstract

Lanthipeptides are an important group of natural products with diverse biological functions, and their biosynthesis requires the removal of N-terminal leader peptides (LPs) by designated proteases. LanPM1 enzymes, a subgroup of M1 zinc-metallopeptidases, have been recently identified as bifunctional proteases with both endo- and aminopeptidase activities to remove LPs of class III and class IV lanthipeptides. Herein, we report the biochemical and structural characterization of EryP as the LanPM1 enzyme from the biosynthesis of class III lanthipeptide erythreapeptin. We determined X-ray crystal structures of EryP in three conformational states, the open, intermediate and closed states, and identified a unique interdomain Ca2+ binding site as a regulatory element that modulates its domain dynamics and proteolytic activity. Inspired by this regulatory Ca2+ binding, we developed a strategy to engineer LanPM1 enzymes for enhanced catalytic activities by strengthening interdomain associations and driving the conformational equilibrium toward their closed forms.

Reviews citing this publication (2)

  1. Recent Developments in Zn-Based Biodegradable Materials for Biomedical Applications. Hussain M, Ullah S, Raza MR, Abbas N, Ali A. J Funct Biomater 14 1 (2022)
  2. Synthetic biology-inspired cell engineering in diagnosis, treatment, and drug development. Zhao N, Song Y, Xie X, Zhu Z, Duan C, Nong C, Wang H, Bao R. Signal Transduct Target Ther 8 112 (2023)

Articles citing this publication (1)

  1. Discovery and biosynthesis of tricyclic copper-binding ribosomal peptides containing histidine-to-butyrine crosslinks. Li Y, Ma Y, Xia Y, Zhang T, Sun S, Gao J, Yao H, Wang H. Nat Commun 14 2944 (2023)


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