1u7t
From Proteopedia
Crystal Structure of ABAD/HSD10 with a Bound Inhibitor
Structural highlights
Disease[HCD2_HUMAN] Defects in HSD17B10 are the cause of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (MHBD deficiency) [MIM:300438]. MHBD deficiency leads to neurological abnormalities, including psychomotor retardation, and, in virtually all patients, loss of mental and motor skills. Defects in HSD17B10 are the cause of mental retardation syndromic X-linked type 10 (MRXS10) [MIM:300220]. MRXS10 is characterized by mild mental retardation, choreoathetosis and abnormal behavior.[1] A chromosomal microduplication involving HSD17B10 and HUWE1 is the cause of mental retardation X-linked type 17 (MRX17) [MIM:300705]; also known as mental retardation X-linked type 31 (MRX31). Mental retardation is characterized by significantly sub-average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. In contrast to syndromic or specific X-linked mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation.[2] Function[HCD2_HUMAN] Functions in mitochondrial tRNA maturation. Part of mitochondrial ribonuclease P, an enzyme composed of MRPP1/TRMT10C, MRPP2/HSD17B10 and MRPP3/KIAA0391, which cleaves tRNA molecules in their 5'-ends. By interacting with intracellular amyloid-beta, it may contribute to the neuronal dysfunction associated with Alzheimer disease (AD).[3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe enzyme 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), also known as amyloid beta-peptide-binding alcohol dehydrogenase (ABAD), has been implicated in the development of Alzheimer's disease. This protein, a member of the short-chain dehydrogenase/reductase family of enzymes, has been shown to bind beta-amyloid and to participate in beta-amyloid neurotoxicity. We have determined the crystal structure of human ABAD/HSD10 complexed with NAD(+) and an inhibitory small molecule. The inhibitor occupies the substrate-binding site and forms a covalent adduct with the NAD(+) cofactor. The crystal structure provides a basis for the design of potent, highly specific ABAD/HSD10 inhibitors with potential application in the treatment of Alzheimer's disease. Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics.,Kissinger CR, Rejto PA, Pelletier LA, Thomson JA, Showalter RE, Abreo MA, Agree CS, Margosiak S, Meng JJ, Aust RM, Vanderpool D, Li B, Tempczyk-Russell A, Villafranca JE J Mol Biol. 2004 Sep 17;342(3):943-52. PMID:15342248[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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