8G6C

GTP Cyclohydrolase-IB with manganese

これはPDB形式変換不可エントリーです。

8G6C の概要

• エントリーDOI: 10.2210/pdb8g6c/pdb
• 分子名称: GTP cyclohydrolase FolE2, MANGANESE (II) ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: cyclohydrolase, gtp, manganese, fole2, hydrolase
• 由来する生物種: Burkholderia pseudomallei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68291.17

構造登録者

McWhorter, K.L.,Amaya Lopez, C.Y.,Davis, K.M. (登録日: 2023-02-14, 公開日: 2024-02-21, 最終更新日: 2024-11-20)

主引用文献

Zhang, Y.,McWhorter, K.L.,Rosen, P.C.,Klaus, J.R.,Gallant, E.,Amaya Lopez, C.Y.,Jhunjhunwala, R.,Chandler, J.R.,Davis, K.M.,Seyedsayamdost, M.R.
Combatting melioidosis with chemical synthetic lethality.
Proc.Natl.Acad.Sci.USA, 121:e2406771121-e2406771121, 2024

PubMed Abstract: has emerged as a nonpathogenic surrogate for , the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome of . In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential for in the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and β-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity against . Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.

PubMed: 39495920
DOI: 10.1073/pnas.2406771121

実験手法

X-RAY DIFFRACTION (2.82 Å)