Crystal structure of human ABAD/HSD10 with a bound inhibitor: Implications for design of Alzheimer's disease therapeutics

被引：88

作者：

Kissinger, CR ^{[1
]}

Rejto, PA ^{[1
]}

Pelletier, LA ^{[1
]}

Thomson, JA ^{[1
]}

Showalter, RE ^{[1
]}

Abreo, MA ^{[1
]}

Agree, CS ^{[1
]}

Margosiak, S ^{[1
]}

Meng, JJ ^{[1
]}

Vanderpool, RMAD ^{[1
]}

Li, B ^{[1
]}

Tempczyk-Russell, A ^{[1
]}

Villafranca, JE ^{[1
]}

机构：

[1] Pfizer, La Jolla, CA USA

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2004年 / 342卷 / 03期

关键词：

ABAD; HSD10; Alzheimer's disease; short-chain dehydrogenase;

D O I：

10.1016/j.jmb.2004.07.071

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The 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. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：943 / 952

页数：10

共 41 条

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