8V2T

Phosphoheptose isomerase GMHA from Burkholderia pseudomallei bound to inhibitor Mut148591

8V2T の概要

• エントリーDOI: 10.2210/pdb8v2t/pdb
• 関連するPDBエントリー: 8V4J
• 分子名称: Phosphoheptose isomerase, 1,5,6-trideoxy-6,6-difluoro-1-(N-hydroxyformamido)-6-phosphono-D-ribo-hexitol, ZINC ION, ... (6 entities in total)
• 機能のキーワード: heptose biosynthesis, isomerase-inhibitor complex, isomerase/inhibitor
• 由来する生物種: Burkholderia pseudomallei 1106a
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23826.51

構造登録者

Junop, M.S.,Brown, C.,Szabla, R. (登録日: 2023-11-23, 公開日: 2023-12-06, 最終更新日: 2024-05-01)

主引用文献

Moreau, F.,Atamanyuk, D.,Blaukopf, M.,Barath, M.,Herczeg, M.,Xavier, N.M.,Monbrun, J.,Airiau, E.,Henryon, V.,Leroy, F.,Floquet, S.,Bonnard, D.,Szabla, R.,Brown, C.,Junop, M.S.,Kosma, P.,Gerusz, V.
Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.
J.Med.Chem., 67:6610-6623, 2024

PubMed Abstract: Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d--d--heptose 7-phosphate and harbors a Zn ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two -formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in as well as the potentiation of erythromycin and rifampicin in a wild-type strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

PubMed: 38598312
DOI: 10.1021/acs.jmedchem.4c00037

実験手法

X-RAY DIFFRACTION (1.402 Å)