7UCH

AprA Methyltransferase 1 - GNAT in complex with Mn2+ , SAM, and Di-methyl-malonate

Summary for 7UCH

• Entry DOI: 10.2210/pdb7uch/pdb
• Related: 6B39 6B3A 6B3B
• Descriptor: AprA Methyltransferase 1, MANGANESE (II) ION, GLYCEROL, ... (6 entities in total)
• Functional Keywords: polyketide synthase, transferase
• Biological source: Moorena bouillonii
• Total number of polymer chains: 1
• Total formula weight: 75489.39

Authors

Skiba, M.A.,Lao, Y.,Smith, J.L. (deposition date: 2022-03-16, release date: 2022-06-01, Last modification date: 2023-10-18)

Primary citation

Lao, Y.,Skiba, M.A.,Chun, S.W.,Narayan, A.R.H.,Smith, J.L.
Structural Basis for Control of Methylation Extent in Polyketide Synthase Metal-Dependent C -Methyltransferases.
Acs Chem.Biol., 17:2088-2098, 2022

PubMed Abstract: Installation of methyl groups can significantly improve the binding of small-molecule drugs to protein targets; however, site-selective methylation often presents a significant synthetic challenge. Metal- and -adenosyl-methionine (SAM)-dependent methyltransferases (MTs) in natural-product biosynthetic pathways are powerful enzymatic tools for selective or chemically challenging C-methylation reactions. Each of these MTs selectively catalyzes one or two methyl transfer reactions. Crystal structures and biochemical assays of the Mn-dependent monomethyltransferase from the saxitoxin biosynthetic pathway (SxtA MT) revealed the structural basis for control of methylation extent. The SxtA monomethyltransferase was converted to a dimethyltransferase by modification of the metal binding site, addition of an active site base, and an amino acid substitution to provide space in the substrate pocket for two methyl substituents. A reciprocal change converted a related dimethyltransferase into a monomethyltransferase, supporting our hypothesis that steric hindrance can prevent a second methylation event. A novel understanding of MTs will accelerate the development of MT-based catalysts and MT engineering for use in small-molecule synthesis.

PubMed: 35594521
DOI: 10.1021/acschembio.2c00085

Experimental method

X-RAY DIFFRACTION (2.18 Å)