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| | <StructureSection load='6plg' size='340' side='right'caption='[[6plg]], [[Resolution|resolution]] 2.93Å' scene=''> | | <StructureSection load='6plg' size='340' side='right'caption='[[6plg]], [[Resolution|resolution]] 2.93Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6plg]] 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=6PLG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PLG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6plg]] is a 8 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=6PLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PLG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MLT:D-MALATE'>MLT</scene>, <scene name='pdbligand=ONS:(2S)-(4-{3-[(4,5-dichloro-1-methyl-1H-indole-2-carbonyl)amino]oxetan-3-yl}phenyl)(pyridin-3-yl)acetic+acid'>ONS</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]] 2.93Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PHGDH, PGDH3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLT:D-MALATE'>MLT</scene>, <scene name='pdbligand=ONS:(2~{S})-2-[4-[3-[[4,5-bis(chloranyl)-1-methyl-indol-2-yl]carbonylamino]oxetan-3-yl]phenyl]-2-pyridin-3-yl-ethanoic+acid'>ONS</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6plg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6plg OCA], [http://pdbe.org/6plg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6plg RCSB], [http://www.ebi.ac.uk/pdbsum/6plg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6plg ProSAT]</span></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=6plg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6plg OCA], [https://pdbe.org/6plg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6plg RCSB], [https://www.ebi.ac.uk/pdbsum/6plg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6plg ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SERA_HUMAN SERA_HUMAN]] Defects in PHGDH are the cause of phosphoglycerate dehydrogenase deficiency (PHGDH deficiency) [MIM:[http://omim.org/entry/601815 601815]]. It is characterized by congenital microcephaly, psychomotor retardation, and seizures. | + | [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 == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6plg" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6plg" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Phosphoglycerate dehydrogenase|Phosphoglycerate dehydrogenase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lakshminarasimhan, D]] | + | [[Category: Lakshminarasimhan D]] |
| - | [[Category: Olland, A]] | + | [[Category: Olland A]] |
| - | [[Category: Suto, R K]] | + | [[Category: Suto RK]] |
| - | [[Category: White, A]] | + | [[Category: White A]] |
| - | [[Category: Dehydrogenase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Oxidoreductase-inhibitor complex]]
| + | |
| - | [[Category: Serine metabolism]]
| + | |
| Structural highlights
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.
Function
SERA_HUMAN
Publication Abstract from PubMed
Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD(+) pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.
Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.,Mullarky E, Xu J, Robin AD, Huggins DJ, Jennings A, Noguchi N, Olland A, Lakshminarasimhan D, Miller M, Tomita D, Michino M, Su T, Zhang G, Stamford AW, Meinke PT, Kargman S, Cantley LC Bioorg Med Chem Lett. 2019 Jul 6. pii: S0960-894X(19)30456-1. doi:, 10.1016/j.bmcl.2019.07.011. PMID:31327531[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Mullarky E, Xu J, Robin AD, Huggins DJ, Jennings A, Noguchi N, Olland A, Lakshminarasimhan D, Miller M, Tomita D, Michino M, Su T, Zhang G, Stamford AW, Meinke PT, Kargman S, Cantley LC. Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells. Bioorg Med Chem Lett. 2019 Jul 6. pii: S0960-894X(19)30456-1. doi:, 10.1016/j.bmcl.2019.07.011. PMID:31327531 doi:http://dx.doi.org/10.1016/j.bmcl.2019.07.011
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