5ofm

Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 5-amino-1-methyl-1H-indole

spinqualitylabelsall models 5ofm, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ofm is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9TT Gene: PHGDH, PGDH3 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [SERA_HUMAN] Defects in PHGDH are the cause of phosphoglycerate dehydrogenase deficiency (PHGDH deficiency) [MIM:601815]. It is characterized by congenital microcephaly, psychomotor retardation, and seizures. Publication Abstract from PubMed 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 PHGDH-amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH-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. Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer.,Unterlass JE, Basle A, Blackburn TJ, Tucker J, Cano C, Noble ME, Curtin NJ Oncotarget. 2016 Aug 22. doi: 10.18632/oncotarget.11487. PMID:27564259 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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