5UQ9

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

Summary for 5UQ9

• Entry DOI: 10.2210/pdb5uq9/pdb
• Related: 2JKV 4GWG 4GWK
• Descriptor: 6-phosphogluconate dehydrogenase, decarboxylating, [(4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl dihydrogen phosphate (2 entities in total)
• Functional Keywords: rossmann fold, pentose phosphate pathway, dehydrogenase, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 430379.19

Authors

Leonard, P.G. (deposition date: 2017-02-07, release date: 2018-08-22, Last modification date: 2023-10-04)

Primary citation

Sun, Y.,Bandi, M.,Lofton, T.,Smith, M.,Bristow, C.A.,Carugo, A.,Rogers, N.,Leonard, P.,Chang, Q.,Mullinax, R.,Han, J.,Shi, X.,Seth, S.,Meyers, B.A.,Miller, M.,Miao, L.,Ma, X.,Feng, N.,Giuliani, V.,Geck Do, M.,Czako, B.,Palmer, W.S.,Mseeh, F.,Asara, J.M.,Jiang, Y.,Morlacchi, P.,Zhao, S.,Peoples, M.,Tieu, T.N.,Warmoes, M.O.,Lorenzi, P.L.,Muller, F.L.,DePinho, R.A.,Draetta, G.F.,Toniatti, C.,Jones, P.,Heffernan, T.P.,Marszalek, J.R.
Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.
Cell Rep, 26:469-482.e5, 2019

PubMed Abstract: 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.

PubMed: 30625329
DOI: 10.1016/j.celrep.2018.12.043

Experimental method

X-RAY DIFFRACTION (3 Å)