7RUE

DAHP synthase complexed with trifluoropyruvate semicarbazone

7RUE の概要

• エントリーDOI: 10.2210/pdb7rue/pdb
• 分子名称: Phospho-2-dehydro-3-deoxyheptonate aldolase, Phe-sensitive, (2E)-2-(2-carbamoylhydrazinylidene)-3,3,3-trifluoropropanoic acid, MANGANESE (II) ION, ... (4 entities in total)
• 機能のキーワード: dahp synthase, inhibitor complex, lyase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Escherichia coli (strain K12)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 153482.32

構造登録者

Heimhalt, M.,Mukherjee, P.,Grainger, R.,Szabla, R.,Brown, C.,Turner, R.,Junop, M.S.,Berti, P.J. (登録日: 2021-08-16, 公開日: 2021-11-17, 最終更新日: 2023-10-18)

主引用文献

Heimhalt, M.,Mukherjee, P.,Grainger, R.A.,Szabla, R.,Brown, C.,Turner, R.,Junop, M.S.,Berti, P.J.
An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition.
Acs Infect Dis., 7:3292-3302, 2021

PubMed Abstract: 3-Deoxy-d-heptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate biosynthetic pathway and is an antimicrobial target. We used an inhibitor-in-pieces approach, based on the previously reported inhibitor DAHP oxime, to screen inhibitor fragments in the presence and absence of glycerol 3-phosphate to occupy the distal end of the active site. This led to DAHP hydrazone, the most potent inhibitor to date, = 10 ± 1 nM. Three trifluoropyruvate (TFP)-based inhibitor fragments were efficient inhibitors with ligand efficiencies of up to 0.7 kcal mol/atom compared with 0.2 kcal mol/atom for a typical good inhibitor. The crystal structures showed the TFP-based inhibitors binding upside down in the active site relative to DAHP oxime, providing new avenues for inhibitor development. The ethyl esters of TFP oxime and TFP semicarbazone prevented growth in culture with IC = 0.21 ± 0.01 and 0.77 ± 0.08 mg mL, respectively. Overexpressing DAHP synthase relieved growth inhibition, demonstrating that DAHP synthase was the target. Growth inhibition occurred in media containing aromatic amino acids, suggesting that growth inhibition was due to depletion of some other product(s) of the shikimate pathway, possibly folate.

PubMed: 34761906
DOI: 10.1021/acsinfecdis.1c00462

実験手法

X-RAY DIFFRACTION (2.5 Å)