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==Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 5-fluoro-2-methylbenzoic acid== | ==Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 5-fluoro-2-methylbenzoic acid== | ||
<StructureSection load='5ofv' size='340' side='right' caption='[[5ofv]], [[Resolution|resolution]] 1.50Å' scene=''> | <StructureSection load='5ofv' size='340' side='right'caption='[[5ofv]], [[Resolution|resolution]] 1.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5ofv]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OFV OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5ofv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5OFV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5OFV FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9TZ:5-fluoranyl-2-methyl-benzoic+acid'>9TZ</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9TZ:5-fluoranyl-2-methyl-benzoic+acid'>9TZ</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ofv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ofv OCA], [https://pdbe.org/5ofv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ofv RCSB], [https://www.ebi.ac.uk/pdbsum/5ofv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ofv ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [https://www.uniprot.org/uniprot/SERA_HUMAN SERA_HUMAN] Defects in PHGDH are the cause of phosphoglycerate dehydrogenase deficiency (PHGDH deficiency) [MIM:[https://omim.org/entry/601815 601815]. It is characterized by congenital microcephaly, psychomotor retardation, and seizures. | ||
== Function == | |||
[https://www.uniprot.org/uniprot/SERA_HUMAN SERA_HUMAN] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == 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. | 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 | 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 MEM, Curtin NJ Oncotarget. 2016 Aug 22;9(17):13139-13153. doi: 10.18632/oncotarget.11487., eCollection 2018 Mar 2. PMID:29568346<ref>PMID:29568346</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 5ofv" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5ofv" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphoglycerate dehydrogenase|Phosphoglycerate dehydrogenase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Basle A]] | ||
[[Category: | [[Category: Blackburn TJ]] | ||
[[Category: | [[Category: Cano C]] | ||
[[Category: | [[Category: Curtin NJ]] | ||
[[Category: | [[Category: Noble MEM]] | ||
[[Category: | [[Category: Tucker J]] | ||
[[Category: | [[Category: Unterlass JE]] | ||
Latest revision as of 19:48, 13 December 2023
Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 5-fluoro-2-methylbenzoic acidCrystal structure of human 3-phosphoglycerate dehydrogenase in complex with 5-fluoro-2-methylbenzoic acid
Structural highlights
DiseaseSERA_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. FunctionPublication Abstract from PubMed3-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 MEM, Curtin NJ Oncotarget. 2016 Aug 22;9(17):13139-13153. doi: 10.18632/oncotarget.11487., eCollection 2018 Mar 2. PMID:29568346[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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