8ITG

Crystal structure of lasso peptide epimerase MslH in complexed with precursor peptide variant MslAW21G

Summary for 8ITG

• Entry DOI: 10.2210/pdb8itg/pdb
• Descriptor: Poly-gamma-glutamate synthesis protein (Capsule biosynthesis protein), Tricyclic peptide MS-271, 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, ... (5 entities in total)
• Functional Keywords: epimerase, mslh, msla, lasso peptide, ripps, ms-271, isomerase
• Biological source: Streptomyces griseorubiginosus; More
• Total number of polymer chains: 2
• Total formula weight: 51920.67

Authors

Nakashima, Y.,Hiroyuki, M. (deposition date: 2023-03-22, release date: 2023-06-21, Last modification date: 2024-10-23)

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 (2.25 Å)