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==Crystal structure of 6-phosphogluconate dehydrogenase with ((4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl dihydrogen phosphate== | ==Crystal structure of 6-phosphogluconate dehydrogenase with ((4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl dihydrogen phosphate== | ||
<StructureSection load='5uq9' size='340' side='right' caption='[[5uq9]], [[Resolution|resolution]] 3.00Å' scene=''> | <StructureSection load='5uq9' size='340' side='right'caption='[[5uq9]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5uq9]] is a 8 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UQ9 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5uq9]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UQ9 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UQ9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8HS:[(4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl+dihydrogen+phosphate'>8HS</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8HS:[(4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl+dihydrogen+phosphate'>8HS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gwg|4gwg]], [[4gwk|4gwk]], [[2jkv|2jkv]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gwg|4gwg]], [[4gwk|4gwk]], [[2jkv|2jkv]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PGD, PGDH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphogluconate_dehydrogenase_(NADP(+)-dependent,_decarboxylating) Phosphogluconate dehydrogenase (NADP(+)-dependent, decarboxylating)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.44 1.1.1.44] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphogluconate_dehydrogenase_(NADP(+)-dependent,_decarboxylating) Phosphogluconate dehydrogenase (NADP(+)-dependent, decarboxylating)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.1.1.44 1.1.1.44] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5uq9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uq9 OCA], [http://pdbe.org/5uq9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uq9 RCSB], [http://www.ebi.ac.uk/pdbsum/5uq9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uq9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/6PGD_HUMAN 6PGD_HUMAN]] Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH. | [[http://www.uniprot.org/uniprot/6PGD_HUMAN 6PGD_HUMAN]] Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH. | ||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:30625329</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5uq9" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[6-phosphogluconate dehydrogenase 3D structures|6-phosphogluconate dehydrogenase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Leonard, P G]] | [[Category: Leonard, P G]] | ||
[[Category: Dehydrogenase]] | [[Category: Dehydrogenase]] | ||
Revision as of 11:21, 30 September 2020
Crystal structure of 6-phosphogluconate dehydrogenase with ((4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl dihydrogen phosphateCrystal structure of 6-phosphogluconate dehydrogenase with ((4R,5R)-5-(hydroxycarbamoyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl dihydrogen phosphate
Structural highlights
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 PubMedThe 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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