5uq9 | pdb_00005uq9

Crystal structure of 6-phosphogluconate dehydrogenase with ((4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl dihydrogen phosphate

spinqualitylabelsall models 5uq9, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5uq9 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: 8HS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function 6PGD_HUMAN Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH. Publication Abstract from PubMed The plasticity of a preexisting regulatory circuit compromises the effectiveness of targeted therapies, and leveraging genetic vulnerabilities in cancer cells may overcome such adaptations. Hereditary leiomyomatosis renal cell carcinoma (HLRCC) is characterized by oxidative phosphorylation (OXPHOS) deficiency caused by fumarate hydratase (FH) nullizyogosity. To identify metabolic genes that are synthetically lethal with OXPHOS deficiency, we conducted a genetic loss-of-function screen and found that phosphogluconate dehydrogenase (PGD) inhibition robustly blocks the proliferation of FH mutant cancer cells both in vitro and in vivo. Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP(+)/NADPH ratio to disrupt redox homeostasis. Furthermore, in the OXPHOS-proficient context, blocking OXPHOS using the small-molecule inhibitor IACS-010759 enhances sensitivity to PGD inhibition in vitro and in vivo. Together, our study reveals a dependency on PGD in OXPHOS-deficient tumors that might inform therapeutic intervention in specific patient populations. Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.,Sun Y, Bandi M, Lofton T, Smith M, Bristow CA, Carugo A, Rogers N, Leonard P, Chang Q, Mullinax R, Han J, Shi X, Seth S, Meyers BA, Miller M, Miao L, Ma X, Feng N, Giuliani V, Geck Do M, Czako B, Palmer WS, Mseeh F, Asara JM, Jiang Y, Morlacchi P, Zhao S, Peoples M, Tieu TN, Warmoes MO, Lorenzi PL, Muller FL, DePinho RA, Draetta GF, Toniatti C, Jones P, Heffernan TP, Marszalek JR Cell Rep. 2019 Jan 8;26(2):469-482.e5. doi: 10.1016/j.celrep.2018.12.043. PMID:30625329 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 6-phosphogluconate dehydrogenase 3D structures

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