8GQB

Crystal structure of lasso peptide epimerase MslH D11A mutant

Summary for 8GQB

• Entry DOI: 10.2210/pdb8gqb/pdb
• Descriptor: Poly-gamma-glutamate synthesis protein (Capsule biosynthesis protein), CALCIUM ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: epimerase, mslh, isomerase
• Biological source: Streptomyces sp.
• Total number of polymer chains: 1
• Total formula weight: 47635.83

Authors

Nakashima, Y.,Morita, H. (deposition date: 2022-08-29, release date: 2023-06-21, Last modification date: 2025-09-17)

Primary citation

Nakashima, Y.,Kawakami, A.,Ogasawara, Y.,Maeki, M.,Tokeshi, M.,Dairi, T.,Morita, H.
Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism.
Nat Commun, 14:4752-4752, 2023

PubMed Abstract: 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.

PubMed: 37550286
DOI: 10.1038/s41467-023-40232-x

Experimental method

X-RAY DIFFRACTION (2.41 Å)