7TWL

Structure of a borosin methyltransferase from Mycena rosella with peptide A2 (MroMA2) in complex with SAH

Summary for 7TWL

• Entry DOI: 10.2210/pdb7twl/pdb
• Descriptor: MroMA2, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: ripps, methyltransferase, borosin, mroma, transferase
• Biological source: Mycena rosella
• Total number of polymer chains: 4
• Total formula weight: 177014.10

Authors

Zheng, Y.,Ongpipattanakul, C.,Nair, S.K. (deposition date: 2022-02-07, release date: 2022-11-02, Last modification date: 2024-10-09)

Primary citation

Zheng, Y.,Ongpipattanakul, C.,Nair, S.K.
Bioconjugate Platform for Iterative Backbone N -Methylation of Peptides.
Acs Catalysis, 12:14006-14014, 2022

PubMed Abstract: -methylation of peptide backbones has often been utilized as a strategy towards the development of peptidic drugs. However, difficulties in the chemical synthesis, high cost of enantiopure -methyl building blocks, and subsequent coupling inefficiencies have hampered larger-scale medicinal chemical efforts. Here, we present a chemoenzymatic strategy for backbone -methylation by bioconjugation of peptides of interest to the catalytic scaffold of a borosin-type methyltransferase. Crystal structures of a substrate tolerant enzyme from guided the design of a decoupled catalytic scaffold that can be linked via a heterobifunctional crosslinker to any peptide substrate of choice. Peptides linked to the scaffold, including those with non-proteinogenic residues, show robust backbone -methylation. Various crosslinking strategies were tested to facilitate substrate disassembly, which enabled a reversible bioconjugation approach that efficiently released modified peptide. Our results provide general framework for the backbone -methylation on any peptide of interest and may facilitate the production of large libraries of -methylated peptides.

PubMed: 36793448
DOI: 10.1021/acscatal.2c04681

Experimental method

X-RAY DIFFRACTION (1.86 Å)