3U16

Structure of BasE N-terminal domain from Acinetobacter baumannii bound to 6-(p-benzyloxy)phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid.

3U16 の概要

• エントリーDOI: 10.2210/pdb3u16/pdb
• 関連するPDBエントリー: 3O82 3O83 3O84 3U17
• 分子名称: Peptide arylation enzyme, 6-[4-(benzyloxy)phenyl]-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: anl superfamily, adenylating enzyme, 2, 3-dihydroxybenzoate:aryl carrier protein ligase, basf, ligase
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 123086.28

構造登録者

Gulick, A.M.,Drake, E.J.,Aldrich, C.C.,Neres, J. (登録日: 2011-09-29, 公開日: 2012-10-03, 最終更新日: 2023-09-13)

主引用文献

Neres, J.,Engelhart, C.A.,Drake, E.J.,Wilson, D.J.,Fu, P.,Boshoff, H.I.,Barry 3rd, C.E.,Gulick, A.M.,Aldrich, C.C.
Non-nucleoside inhibitors of BasE, an adenylating enzyme in the siderophore biosynthetic pathway of the opportunistic pathogen Acinetobacter baumannii.
J.Med.Chem., 56:2385-2405, 2013

PubMed Abstract: Siderophores are small-molecule iron chelators produced by bacteria and other microorganisms for survival under iron limiting conditions such as found in a mammalian host. Siderophore biosynthesis is essential for the virulence of many important Gram-negative pathogens including Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. We performed high-throughput screening against BasE, which is involved in siderophore biosynthesis in A. baumannii, and identified 6-phenyl-1-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid 15. Herein we report the synthesis, biochemical, and microbiological evaluation of a systematic series of analogues of the HTS hit 15. Analogue 67 is the most potent analogue with a KD of 2 nM against BasE. Structural characterization of the inhibitors with BasE reveals that they bind in a unique orientation in the active site, occupying all three substrate binding sites, and thus can be considered as multisubstrate inhibitors. These results provide a foundation for future studies aimed at increasing both enzyme potency and antibacterial activity.

PubMed: 23437866
DOI: 10.1021/jm301709s

実験手法

X-RAY DIFFRACTION (2.1 Å)