6cwa: Difference between revisions
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<StructureSection load='6cwa' size='340' side='right'caption='[[6cwa]], [[Resolution|resolution]] 1.77Å' scene=''> | <StructureSection load='6cwa' size='340' side='right'caption='[[6cwa]], [[Resolution|resolution]] 1.77Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6cwa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CWA OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6cwa]] 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=6CWA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CWA FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PG:3-PHOSPHOGLYCERIC+ACID'>3PG</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</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]] 1.77Å</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=3PG:3-PHOSPHOGLYCERIC+ACID'>3PG</scene>, <scene name='pdbligand=NAI:1,4-DIHYDRONICOTINAMIDE+ADENINE+DINUCLEOTIDE'>NAI</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=6cwa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cwa OCA], [https://pdbe.org/6cwa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cwa RCSB], [https://www.ebi.ac.uk/pdbsum/6cwa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cwa 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 == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6cwa" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6cwa" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphoglycerate dehydrogenase|Phosphoglycerate dehydrogenase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Davies | [[Category: Davies DR]] | ||
[[Category: Edwards | [[Category: Edwards TE]] | ||
Latest revision as of 18:12, 4 October 2023
CRYSTAL STRUCTURE PHGDH IN COMPLEX WITH NADH AND 3-PHOSPHOGLYCERATE AT 1.77 A RESOLUTIONCRYSTAL STRUCTURE PHGDH IN COMPLEX WITH NADH AND 3-PHOSPHOGLYCERATE AT 1.77 A RESOLUTION
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 PubMedPhosphoglycerate 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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