4jnk

From Proteopedia

Lactate Dehydrogenase A in complex with inhibitor compound 22

PDB ID 4jnk

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Structural highlights

4jnk is a 4 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 1.896Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

LDHA_HUMAN Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue.^[1]

Function

LDHA_HUMAN

Publication Abstract from PubMed

A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1muM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48muM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.

Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase.,Dragovich PS, Fauber BP, Corson LB, Ding CZ, Eigenbrot C, Ge H, Giannetti AM, Hunsaker T, Labadie S, Liu Y, Malek S, Pan B, Peterson D, Pitts K, Purkey HE, Sideris S, Ultsch M, Vanderporten E, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X Bioorg Med Chem Lett. 2013 Jun 1;23(11):3186-94. doi: 10.1016/j.bmcl.2013.04.001., Epub 2013 Apr 10. PMID:23628333^[2]

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

References

↑ Maekawa M, Sudo K, Kanno T, Li SS. Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Commun. 1990 Apr 30;168(2):677-82. PMID:2334430
↑ Dragovich PS, Fauber BP, Corson LB, Ding CZ, Eigenbrot C, Ge H, Giannetti AM, Hunsaker T, Labadie S, Liu Y, Malek S, Pan B, Peterson D, Pitts K, Purkey HE, Sideris S, Ultsch M, Vanderporten E, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X. Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase. Bioorg Med Chem Lett. 2013 Jun 1;23(11):3186-94. doi: 10.1016/j.bmcl.2013.04.001., Epub 2013 Apr 10. PMID:23628333 doi:10.1016/j.bmcl.2013.04.001