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Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism
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Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism
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Journal Article
Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism
2023
Overview
The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the
C
-terminus, and is derived from the precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster (
msl
), catalyzes the epimerization at the Cα center of the MslA
C
-terminal Trp21, leading to
epi
-MslA. The detailed catalytic process, including the catalytic site and cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies in association with MslA core peptide analogues, we show that MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold. The crystal structure analysis, followed by site-directed mutagenesis, docking simulation, and ICP-MS studies demonstrate that MslH employs acid/base chemistry to facilitate the reversible epimerization of the
C-
terminal Trp21 of MslA, by utilizing two pairs of His/Asp catalytic residues that are electrostatically tethered to a six-coordination motif with a Ca(II) ion via water molecules.
MslH, encoded in the MS-271 biosynthetic gene cluster, catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, however, the detailed catalytic process was unknown. Here, the authors report MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
