7POE

Phosphoglycolate Phosphatase with Inhibitor CP1

7POE の概要

• エントリーDOI: 10.2210/pdb7poe/pdb
• 関連するPDBエントリー: 7PO7
• 分子名称: Glycerol-3-phosphate phosphatase, 2-[[4-[4-[(2-carboxyphenyl)carbamoyl]phenoxy]phenyl]carbonylamino]benzoic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: pgp, glycerol-3-phosphate phosphatase, aum, inhibitor, hydrolase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71422.37

構造登録者

Schloetzer, J.,Fratz, S.,Schindelin, H. (登録日: 2021-09-08, 公開日: 2022-12-21, 最終更新日: 2024-07-03)

主引用文献

Jeanclos, E.,Schlotzer, J.,Hadamek, K.,Yuan-Chen, N.,Alwahsh, M.,Hollmann, R.,Fratz, S.,Yesilyurt-Gerhards, D.,Frankenbach, T.,Engelmann, D.,Keller, A.,Kaestner, A.,Schmitz, W.,Neuenschwander, M.,Hergenroder, R.,Sotriffer, C.,von Kries, J.P.,Schindelin, H.,Gohla, A.
Glycolytic flux control by drugging phosphoglycolate phosphatase.
Nat Commun, 13:6845-6845, 2022

PubMed Abstract: Targeting the intrinsic metabolism of immune or tumor cells is a therapeutic strategy in autoimmunity, chronic inflammation or cancer. Metabolite repair enzymes may represent an alternative target class for selective metabolic inhibition, but pharmacological tools to test this concept are needed. Here, we demonstrate that phosphoglycolate phosphatase (PGP), a prototypical metabolite repair enzyme in glycolysis, is a pharmacologically actionable target. Using a combination of small molecule screening, protein crystallography, molecular dynamics simulations and NMR metabolomics, we discover and analyze a compound (CP1) that inhibits PGP with high selectivity and submicromolar potency. CP1 locks the phosphatase in a catalytically inactive conformation, dampens glycolytic flux, and phenocopies effects of cellular PGP-deficiency. This study provides key insights into effective and precise PGP targeting, at the same time validating an allosteric approach to control glycolysis that could advance discoveries of innovative therapeutic candidates.

PubMed: 36369173
DOI: 10.1038/s41467-022-34228-2

実験手法

X-RAY DIFFRACTION (3.16 Å)