5DM2

Crystal structure of the plantazolicin methyltransferase BpumL in complex with triazolic desmethylPZN analog and SAH

5DM2 の概要

• エントリーDOI: 10.2210/pdb5dm2/pdb
• 関連するPDBエントリー: 5DLY 5DM1 5DM4
• 分子名称: Methyltransferase domain family, S-ADENOSYL-L-HOMOCYSTEINE, ethyl 2-(2-{2-[(1S)-4-carbamimidamido-1-(methylamino)butyl]-1,3-thiazol-4-yl}-5-methyl-1,3-oxazol-4-yl)-1,3-thiazole-4-carboxylate, ... (5 entities in total)
• 機能のキーワード: n-methyltransferase, plantazolicin, triazolic desmethylpzn analog, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Bacillus pumilus ATCC 7061
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31325.66

構造登録者

Hao, Y.,Nair, S.K. (登録日: 2015-09-07, 公開日: 2015-09-23, 最終更新日: 2024-03-13)

主引用文献

Hao, Y.,Blair, P.M.,Sharma, A.,Mitchell, D.A.,Nair, S.K.
Insights into methyltransferase specificity and bioactivity of derivatives of the antibiotic plantazolicin.
Acs Chem.Biol., 10:1209-1216, 2015

PubMed Abstract: Peptide antibiotics represent a class of conformationally constrained natural products of growing pharmaceutical interest. Plantazolicin (PZN) is a linear, polyheterocyclic natural product with highly selective and potent activity against the anthrax-causing bacterium, Bacillus anthracis. The bioactivity of PZN is contingent on dimethylation of its N-terminal Arg residue by an S-adenosylmethionine-dependent methyltransferase. Here, we explore the substrate tolerances of two homologous PZN methyltransferases by carrying out kinetic analyses of the enzymes against a synthetic panel of truncated PZN analogs containing the N-terminal Arg residue. X-ray cocrystal structures of the PZN methyltransferases with each of these heterocycle-containing substrates provide a rationale for understanding the strict substrate specificity of these enzymes. Kinetic studies of structure-guided, site-specific variants allowed for the assignment of residues governing catalysis and substrate scope. Microbiological testing further revealed that upon dimethylation of the N-terminal Arg, a pentaheterocyclized PZN analog retained potent anti-B. anthracis activity, nearly equal to that of full-length PZN. These studies may be useful in the biosynthetic engineering of natural product analogs with different bioactivity profiles, as demonstrated by our identification of a truncated plantazolicin derivative that is active against methicillin-resistant Staphylococcus aureus (MRSA).

PubMed: 25635336
DOI: 10.1021/cb501042a

実験手法

X-RAY DIFFRACTION (1.5 Å)