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Publication Abstract from PubMed

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 Calpha 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.

Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism.,Nakashima Y, Kawakami A, Ogasawara Y, Maeki M, Tokeshi M, Dairi T, Morita H Nat Commun. 2023 Aug 8;14(1):4752. doi: 10.1038/s41467-023-40232-x. PMID:37550286^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.