3V7C

Cystal structure of SaBPL in complex with inhibitor

3V7C の概要

• エントリーDOI: 10.2210/pdb3v7c/pdb
• 関連するPDBエントリー: 3V7R 3V7S 3V8J 3V8K 3V8L
• 分子名称: Biotin ligase, 5'-deoxy-2',3'-O-(1-methylethylidene)-5'-(4-{5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentyl}-1H-1,2,3-triazol-1-yl)adenosine (3 entities in total)
• 機能のキーワード: biotin, metabolism, biotin carboxyl carrier protein, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 38585.50

構造登録者

Yap, M.Y.,Pendini, N.R. (登録日: 2011-12-20, 公開日: 2012-04-18, 最終更新日: 2024-03-20)

主引用文献

Soares da Costa, T.P.,Tieu, W.,Yap, M.Y.,Pendini, N.R.,Polyak, S.W.,Sejer Pedersen, D.,Morona, R.,Turnidge, J.D.,Wallace, J.C.,Wilce, M.C.,Booker, G.W.,Abell, A.D.
Selective inhibition of biotin protein ligase from Staphylococcus aureus.
J.Biol.Chem., 287:17823-17832, 2012

PubMed Abstract: There is a well documented need to replenish the antibiotic pipeline with new agents to combat the rise of drug resistant bacteria. One strategy to combat resistance is to discover new chemical classes immune to current resistance mechanisms that inhibit essential metabolic enzymes. Many of the obvious drug targets that have no homologous isozyme in the human host have now been investigated. Bacterial drug targets that have a closely related human homologue represent a new frontier in antibiotic discovery. However, to avoid potential toxicity to the host, these inhibitors must have very high selectivity for the bacterial enzyme over the human homolog. We have demonstrated that the essential enzyme biotin protein ligase (BPL) from the clinically important pathogen Staphylococcus aureus could be selectively inhibited. Linking biotin to adenosine via a 1,2,3 triazole yielded the first BPL inhibitor selective for S. aureus BPL over the human equivalent. The synthesis of new biotin 1,2,3-triazole analogues using click chemistry yielded our most potent structure (K(i) 90 nM) with a >1100-fold selectivity for the S. aureus BPL over the human homologue. X-ray crystallography confirmed the mechanism of inhibitor binding. Importantly, the inhibitor showed cytotoxicity against S. aureus but not cultured mammalian cells. The biotin 1,2,3-triazole provides a novel pharmacophore for future medicinal chemistry programs to develop this new antibiotic class.

PubMed: 22437830
DOI: 10.1074/jbc.M112.356576

実験手法

X-RAY DIFFRACTION (2.7 Å)