3G2P

Crystal Structure of the Glycopeptide N-methyltransferase MtfA complexed with (S)-adenosyl-L-homocysteine (SAH)

Summary for 3G2P

• Entry DOI: 10.2210/pdb3g2p/pdb
• Related: 3G2M 3G2O 3G2Q
• Descriptor: PCZA361.24, S-ADENOSYL-L-HOMOCYSTEINE (3 entities in total)
• Functional Keywords: sam-dependent methyltransferase, glycopeptide antibiotics biosynthesis, structural genomics, montreal-kingston bacterial structural genomics initiative, bsgi, transferase
• Biological source: Amycolatopsis orientalis
• Total number of polymer chains: 2
• Total formula weight: 65824.08

Authors

Shi, R.,Matte, A.,Cygler, M.,Montreal-Kingston Bacterial Structural Genomics Initiative (BSGI) (deposition date: 2009-01-31, release date: 2009-05-05, Last modification date: 2023-09-06)

Primary citation

Shi, R.,Lamb, S.S.,Zakeri, B.,Proteau, A.,Cui, Q.,Sulea, T.,Matte, A.,Wright, G.D.,Cygler, M.
Structure and function of the glycopeptide N-methyltransferase MtfA, a tool for the biosynthesis of modified glycopeptide antibiotics.
Chem.Biol., 16:401-410, 2009

PubMed Abstract: There is a considerable interest in the modification of existing antibiotics to generate new antimicrobials. Glycopeptide antibiotics (GPAs) are effective against serious Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus. However, resistance to these antibiotics is becoming a serious problem requiring new strategies. We show that the Amycolatopsis orientalis (S)-adenosyl-L-methionine-dependent methyltransferase MtfA, from the vancomycin-class GPA chloroeremomycin biosynthetic pathway, catalyzes in vivo and in vitro methyl transfer to generate methylated GPA derivatives of the teicoplanin class. The crystal structure of MtfA complexed with (S)-adenosyl-L-methionine, (S)-adenosylhomocysteine, or sinefungin inhibitor, coupled with mutagenesis, identified His228 as a likely general base required for methyl transfer to the N terminus of the glycopeptide. Computational docking and molecular dynamics simulations were used to model binding of demethyl-vancomycin aglycone to MtfA. These results demonstrate its utility as a tool for engineering methylated analogs of GPAs.

PubMed: 19389626
DOI: 10.1016/j.chembiol.2009.02.007

Experimental method

X-RAY DIFFRACTION (2.95 Å)