9L4Q

Crystal structure of the carbamoyl N-methyltransferase Asc-Orf2 complexed with SAH

Summary for 9L4Q

• Entry DOI: 10.2210/pdb9l4q/pdb
• Descriptor: Methyltransferase small domain-containing protein, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: n-methyltransferse, post-modification, biosynthetic protein
• Biological source: Amycolatopsis alba DSM 44262
• Total number of polymer chains: 2
• Total formula weight: 48364.76

Authors

Li, Z.Y.,Zhu, D.Y.,Shen, Y.M. (deposition date: 2024-12-20, release date: 2025-10-29)

Primary citation

Li, Z.,Yang, W.,Sun, Z.,Wang, H.,Lu, C.,Zhu, D.,Shen, Y.
A Carbamoyl N -Methyltransferase Catalyzes N -Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis.
J.Am.Chem.Soc., 147:24186-24192, 2025

PubMed Abstract: Primary amide-specific -methyltransferases are extremely scarce in microbial secondary metabolism. Here, Asc-Orf2, an -methyltransferase involved in the biosynthesis of ansacarbamitocins, was identified to catalyze the methylation of the 3--carbamoyl moiety. Structural analysis identified an unprecedented NPPH catalytic motif, offering a mechanistic basis to overcome the chemical inertness of primary amides. The 3--(-methyl)-carbamoyl maytansinoid derivatives, modified Asc-Orf2-catalyzed methylation, exhibited markedly enhanced antitumor activity, highlighting the magic methylation effect in bioactivity modulation. Furthermore, structure-targeted engineering expanded the catalytic scope of Asc-Orf2, enabling the directed synthesis of an -allylated carbamoyl maytansinoid derivative optimized for antibody-drug conjugate payload.

PubMed: 40601550
DOI: 10.1021/jacs.5c05398

Experimental method

X-RAY DIFFRACTION (2.27 Å)