8V9I

1-deoxy-D-xylulose 5-phosphate synthase (DXPS) from Deinococcus radiodurans with D-phenylalanine-derived triazole acetylphosphonate (D-PheTrAP) bound

これはPDB形式変換不可エントリーです。

8V9I の概要

• エントリーDOI: 10.2210/pdb8v9i/pdb
• 分子名称: 1-deoxy-D-xylulose-5-phosphate synthase, 3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-2-{(1S)-1-[(S)-(2-{1-[(1R)-1-carboxy-2-phenylethyl]-1H-1,2,3-triazol-4-yl}ethoxy)(hydroxy)phosphoryl]-1-hydroxyethyl}-5-(2-{[(S)-hydroxy(phosphonooxy)phosphoryl]oxy}ethyl)-4-methyl-1,3-thiazol-3-ium, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: 1-deoxy-d-xylulose 5-phosphate synthase, dxps, thiamine diphosphate, thiamine pyrophosphate, thdp, tpp, the mep pathway, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Deinococcus radiodurans
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 141844.94

構造登録者

Chen, P.Y.-T.,Drennan, C.L. (登録日: 2023-12-08, 公開日: 2024-04-24, 最終更新日: 2025-12-24)

主引用文献

Coco, L.B.,Toci, E.M.,Chen, P.Y.,Drennan, C.L.,Freel Meyers, C.L.
Potent Inhibition of E. coli DXP Synthase by a gem -Diaryl Bisubstrate Analog.
Acs Infect Dis., 10:1312-1326, 2024

PubMed Abstract: New antimicrobial strategies are needed to address pathogen resistance to currently used antibiotics. Bacterial central metabolism is a promising target space for the development of agents that selectively target bacterial pathogens. 1-Deoxy-d-xylulose 5-phosphate synthase (DXPS) converts pyruvate and d-glyceraldehyde 3-phosphate (d-GAP) to DXP, which is required for synthesis of essential vitamins and isoprenoids in bacterial pathogens. Thus, DXPS is a promising antimicrobial target. Toward this goal, our lab has demonstrated selective inhibition of DXPS by alkyl acetylphosphonate (alkylAP)-based bisubstrate analogs that exploit the requirement for ternary complex formation in the DXPS mechanism. Here, we present the first DXPS structure with a bisubstrate analog bound in the active site. Insights gained from this cocrystal structure guided structure-activity relationship studies of the bisubstrate scaffold. A low nanomolar inhibitor (compound ) bearing a -dibenzyl glycine moiety conjugated to the acetylphosphonate pyruvate mimic via a triazole-based linker emerged from this study. Compound was found to exhibit slow, tight-binding inhibition, with contacts to DXPS residues R99 and R478 demonstrated to be important for this behavior. This work has discovered the most potent DXPS inhibitor to date and highlights a new role of R99 that can be exploited in future inhibitor designs toward the development of a novel class of antimicrobial agents.

PubMed: 38513073
DOI: 10.1021/acsinfecdis.3c00734

実験手法

X-RAY DIFFRACTION (1.981 Å)