5NZO
Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 1-methyl-3-phenyl-1H-pyrazol-5-amine
Summary for 5NZO
| Entry DOI | 10.2210/pdb5nzo/pdb |
| Descriptor | D-3-phosphoglycerate dehydrogenase, 2-methyl-5-phenyl-pyrazol-3-amine (3 entities in total) |
| Functional Keywords | dehydrogenase, serine metabolism, fbdd, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 42250.64 |
| Authors | Unterlass, J.E.,Basle, A.,Blackburn, T.J.,Tucker, J.,Cano, C.,Noble, M.E.M.,Curtin, N.J. (deposition date: 2017-05-14, release date: 2017-06-14, Last modification date: 2024-01-17) |
| Primary citation | Unterlass, J.E.,Basle, A.,Blackburn, T.J.,Tucker, J.,Cano, C.,Noble, M.E.M.,Curtin, N.J. Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer. Oncotarget, 9:13139-13153, 2018 Cited by PubMed Abstract: 3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in -amplified breast cancer. Knockdown caused reduced proliferation in the -amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected. As a first step towards design of a chemical probe for PHGDH, we report a fragment-based drug discovery approach for the identification of PHGDH inhibitors. We designed a truncated PHGDH construct that gave crystals which diffracted to high resolution, and could be used for fragment soaking. 15 fragments stabilising PHGDH were identified using a thermal shift assay and validated by X-ray crystallography and ITC competition experiments to exhibit 1.5-26.2 mM affinity for PHGDH. A structure-guided fragment growing approach was applied to the PHGDH binders from the initial screen, yielding greater understanding of the binding site and suggesting routes to achieve higher affinity NAD-competitive inhibitors. PubMed: 29568346DOI: 10.18632/oncotarget.11487 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.29 Å) |
Structure validation
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