7POE
Phosphoglycolate Phosphatase with Inhibitor CP1
Summary for 7POE
| Entry DOI | 10.2210/pdb7poe/pdb |
| Related | 7PO7 |
| Descriptor | Glycerol-3-phosphate phosphatase, 2-[[4-[4-[(2-carboxyphenyl)carbamoyl]phenoxy]phenyl]carbonylamino]benzoic acid, GLYCEROL, ... (5 entities in total) |
| Functional Keywords | pgp, glycerol-3-phosphate phosphatase, aum, inhibitor, hydrolase |
| Biological source | Mus musculus (Mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 71422.37 |
| Authors | Schloetzer, J.,Fratz, S.,Schindelin, H. (deposition date: 2021-09-08, release date: 2022-12-21, Last modification date: 2024-07-03) |
| Primary citation | 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 Cited by 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: 36369173DOI: 10.1038/s41467-022-34228-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.16 Å) |
Structure validation
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