6rj2

Crystal structure of PHGDH in complex with compound 40Crystal structure of PHGDH in complex with compound 40

Structural highlights

6rj2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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. Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis. J Med Chem. 2019 Jul 31. doi: 10.1021/acs.jmedchem.9b00718. PMID:31365252 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00718

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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. Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor BI-4924 Disrupts Serine Biosynthesis. J Med Chem. 2019 Jul 31. doi: 10.1021/acs.jmedchem.9b00718. PMID:31365252 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00718

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