6rj2: Difference between revisions
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<StructureSection load='6rj2' size='340' side='right'caption='[[6rj2]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='6rj2' size='340' side='right'caption='[[6rj2]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6rj2]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RJ2 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6rj2]] 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=6RJ2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RJ2 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K52:~{N}-[(1~{R})-1-[4-(ethanoylsulfamoyl)phenyl]ethyl]-2-methyl-5-phenyl-pyrazole-3-carboxamide'>K52</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K52:~{N}-[(1~{R})-1-[4-(ethanoylsulfamoyl)phenyl]ethyl]-2-methyl-5-phenyl-pyrazole-3-carboxamide'>K52</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6rj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rj2 OCA], [http://pdbe.org/6rj2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rj2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rj2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rj2 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=6rj2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rj2 OCA], [http://pdbe.org/6rj2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rj2 RCSB], [http://www.ebi.ac.uk/pdbsum/6rj2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rj2 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 == | |||
Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate limiting enzyme in the serine synthesis pathway (SSP) in humans. It converts glycolysis derived 3-phosphoglycerate to 3-phosphopyruvate in a NADH/NAD(+)-dependent oxidation reaction. Herein we report the discovery of BI-4916, a prodrug of the NADH/NAD(+)-competitive PHGDH inhibitor BI-4924 which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening (FBS) a subsequent hit optimization using structure based drug design (SBDD) was conducted to deliver a single digit nanomolar lead series and to improve potency by six orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD(+). | |||
Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis.,Weinstabl H, Treu M, Rinnenthal J, Zahn S, Ettmayer P, Bader G, Dahmann G, Kessler D, Rumpel K, Mischerikow N, Savarese F, Gerstberger T, Mayer M, Zoephel A, Schnitzer R, Sommergruber W, Martinelli P, Arnhof H, Peric Simov B, Hofbauer KS, Garavel G, Scherbantin Y, Mitzner S, Fett T, Scholz G, Bruchhaus J, Burkard M, Kousek R, Ciftci T, Sharps B, Schrenk A, Harrer C, Haering D, Wolkerstorfer B, Zhang X, Lv X, Du A, Li D, Li Y, Quant J, Pearson M, McConnell DB J Med Chem. 2019 Jul 31. doi: 10.1021/acs.jmedchem.9b00718. PMID:31365252<ref>PMID:31365252</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6rj2" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bader, G]] | [[Category: Bader, G]] | ||