3SSN

MycE Methyltransferase from the Mycinamycin Biosynthetic Pathway in Complex with Mg, SAH, and Mycinamycin VI

Summary for 3SSN

• Entry DOI: 10.2210/pdb3ssn/pdb
• Related: 3SSM 3SSO
• Descriptor: Methyltransferase, MAGNESIUM ION, S-ADENOSYL-L-HOMOCYSTEINE, ... (7 entities in total)
• Functional Keywords: methyltransferase, macrolide, natural product, rossmann fold, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Micromonospora griseorubida
• Total number of polymer chains: 4
• Total formula weight: 191030.75

Authors

Akey, D.L.,Smith, J.L. (deposition date: 2011-07-08, release date: 2011-08-24, Last modification date: 2024-02-28)

Primary citation

Akey, D.L.,Li, S.,Konwerski, J.R.,Confer, L.A.,Bernard, S.M.,Anzai, Y.,Kato, F.,Sherman, D.H.,Smith, J.L.
A new structural form in the SAM/metal-dependent o‑methyltransferase family: MycE from the mycinamicin biosynthetic pathway.
J.Mol.Biol., 413:438-450, 2011

PubMed Abstract: O-linked methylation of sugar substituents is a common modification in the biosynthesis of many natural products and is catalyzed by multiple families of S-adenosyl-L-methionine (SAM or AdoMet)-dependent methyltransferases (MTs). Mycinamicins, potent antibiotics from Micromonospora griseorubida, can be methylated at two positions on a 6-deoxyallose substituent. The first methylation is catalyzed by MycE, a SAM- and metal-dependent MT. Crystal structures were determined for MycE bound to the product S-adenosyl-L-homocysteine (AdoHcy) and magnesium, both with and without the natural substrate mycinamicin VI. This represents the first structure of a natural product sugar MT in complex with its natural substrate. MycE is a tetramer of a two-domain polypeptide, comprising a C-terminal catalytic MT domain and an N-terminal auxiliary domain, which is important for quaternary assembly and for substrate binding. The symmetric MycE tetramer has a novel MT organization in which each of the four active sites is formed at the junction of three monomers within the tetramer. The active-site structure supports a mechanism in which a conserved histidine acts as a general base, and the metal ion helps to position the methyl acceptor and to stabilize a hydroxylate intermediate. A conserved tyrosine is suggested to support activity through interactions with the transferred methyl group from the SAM methyl donor. The structure of the free enzyme reveals a dramatic order-disorder transition in the active site relative to the S-adenosyl-L-homocysteine complexes, suggesting a mechanism for product/substrate exchange through concerted movement of five loops and the polypeptide C-terminus.

PubMed: 21884704
DOI: 10.1016/j.jmb.2011.08.040

Experimental method

X-RAY DIFFRACTION (2.392 Å)