4OON

Crystal structure of PBP1a in complex with compound 17 ((4Z,8S,11E,14S)-5-(2-amino-1,3-thiazol-4-yl)-14-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-formyl-2-methyl-6-oxo-3,10-dioxa-4,7,11-triazatetradeca-4,11-diene-2,12,14-tricarboxylic acid)

4OON の概要

• エントリーDOI: 10.2210/pdb4oon/pdb
• 関連するPDBエントリー: 4OOL 4OOM
• 分子名称: Penicillin-binding protein 1A, (4Z,8S,11E,14S)-5-(2-amino-1,3-thiazol-4-yl)-14-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-8-formyl-2-methyl-6-oxo-3,10-dioxa-4,7,11-triazatetradeca-4,11-diene-2,12,14-tricarboxylic acid (3 entities in total)
• 機能のキーワード: pbp1a, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Pseudomonas aeruginosa PAO1
• 細胞内の位置: Cell inner membrane; Single-pass type II membrane protein (By similarity): Q07806
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 89044.30

構造登録者

Han, S.,Caspers, N.,Knafels, J.D. (登録日: 2014-02-03, 公開日: 2014-05-07, 最終更新日: 2024-11-20)

主引用文献

Starr, J.,Brown, M.F.,Aschenbrenner, L.,Caspers, N.,Che, Y.,Gerstenberger, B.S.,Huband, M.,Knafels, J.D.,Lemmon, M.M.,Li, C.,McCurdy, S.P.,McElroy, E.,Rauckhorst, M.R.,Tomaras, A.P.,Young, J.A.,Zaniewski, R.P.,Shanmugasundaram, V.,Han, S.
Siderophore receptor-mediated uptake of lactivicin analogues in gram-negative bacteria.
J.Med.Chem., 57:3845-3855, 2014

PubMed Abstract: Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and β-lactam core structures. Results from drug sensitivity studies with β-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.

PubMed: 24694215
DOI: 10.1021/jm500219c

実験手法

X-RAY DIFFRACTION (3.2 Å)