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4ajp

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4ajp, resolution 2.38Å ()
Ligands: , ,
Activity: L-lactate dehydrogenase, with EC number 1.1.1.27
Related: 1i10, 4aj1, 4aj2, 4aj4, 4aje, 4ajh, 4aji, 4ajj, 4ajk, 4ajl, 4ajn, 4ajo


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Human LDHA in complex with 2-((4-(4-((3-((2-methyl-1,3-benzothiazol- 6yl)amino)-3-oxo-propyl)amino)-4-oxo-butyl)phenyl)methyl)propanedioic acid

Publication Abstract from PubMed

Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

Design and synthesis of novel lactate dehydrogenase a inhibitors by fragment-based lead generation., Ward RA, Brassington C, Breeze AL, Caputo A, Critchlow S, Davies G, Goodwin L, Hassall G, Greenwood R, Holdgate GA, Mrosek M, Norman RA, Pearson S, Tart J, Tucker JA, Vogtherr M, Whittaker D, Wingfield J, Winter J, Hudson K, J Med Chem. 2012 Apr 12;55(7):3285-306. Epub 2012 Mar 26. PMID:22417091

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

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]

About this Structure

4ajp is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Ward RA, Brassington C, Breeze AL, Caputo A, Critchlow S, Davies G, Goodwin L, Hassall G, Greenwood R, Holdgate GA, Mrosek M, Norman RA, Pearson S, Tart J, Tucker JA, Vogtherr M, Whittaker D, Wingfield J, Winter J, Hudson K. Design and synthesis of novel lactate dehydrogenase a inhibitors by fragment-based lead generation. J Med Chem. 2012 Apr 12;55(7):3285-306. Epub 2012 Mar 26. PMID:22417091 doi:10.1021/jm201734r
  1. 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

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