6plf
From Proteopedia
(Difference between revisions)
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<StructureSection load='6plf' size='340' side='right'caption='[[6plf]], [[Resolution|resolution]] 1.70Å' scene=''> | <StructureSection load='6plf' size='340' side='right'caption='[[6plf]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6plf]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PLF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PLF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6plf]] is a 2 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=6PLF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PLF FirstGlance]. <br> |
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ONV:4-{(1S)-1-[(5-chloro-6-{[(5S)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1H-indole-2-carbonyl)amino]-2-hydroxyethyl}benzoic+acid'>ONV</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=ONV:4-{(1S)-1-[(5-chloro-6-{[(5S)-2-oxo-1,3-oxazolidin-5-yl]methoxy}-1H-indole-2-carbonyl)amino]-2-hydroxyethyl}benzoic+acid'>ONV</scene></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='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=6plf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6plf OCA], [http://pdbe.org/6plf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6plf RCSB], [http://www.ebi.ac.uk/pdbsum/6plf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6plf ProSAT]</span></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=6plf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6plf OCA], [http://pdbe.org/6plf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6plf RCSB], [http://www.ebi.ac.uk/pdbsum/6plf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6plf 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. | [[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. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:31327531</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6plf" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Human]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Lakshminarasimhan, D]] | [[Category: Lakshminarasimhan, D]] | ||
Revision as of 06:22, 7 August 2019
Crystal structure of human PHGDH complexed with Compound 1
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