|
ツゲ ヒデアキ
TSUGE HIDEAKI
津下 英明 所属 京都産業大学 生命科学部 先端生命科学科 職種 教授 |
|
| 言語種別 | 英語 |
| 発行・発表の年月 | 2006/12 |
| 形態種別 | 研究論文 |
| 査読 | 査読あり |
| 標題 | Crystal structure of human D-amino acid oxidase: Context-dependent variability of the backbone conformation of the VAAGL hydrophobic stretch located at the si-face of the flavin ring |
| 執筆形態 | その他 |
| 掲載誌名 | PROTEIN SCIENCE |
| 出版社・発行元 | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT |
| 巻・号・頁 | 15(12),pp.2708-2717 |
| 著者・共著者 | Tomoya Kawazoe,Hideaki Tsuge,Mirella S. Pilone,Kiyoshi Fukui |
| 概要 | In the brain, the extensively studied FAD-dependent enzyme D-amino acid oxidase (DAO) degrades the gliotransmitter D-serine, a potent activator of N-methyl-D-aspartate type glutamate receptors, and evidence suggests that DAO, together with its activator G72 protein, may play a key role in the pathophysiology of schizophrenia. Indeed, its potential clinical importance highlights the need for structural and functional analyses of human DAO. We recently succeeded in purifying human DAO, and found that it weakly binds FAD and shows a significant slower rate of flavin reduction compared with porcine DAO. However, the molecular basis for the different kinetic features remains unclear because the active site of human DAO was considered to be virtually identical to that of porcine DAO, as would be expected from the 85% sequence identity. To address this issue, we determined the crystal structure of human DAO in complex with a competitive inhibitor benzoate, at a resolution of 2.5 angstrom. The overall dimeric structure of human DAO is similar to porcine DAO, and the catalytic residues are fully conserved at the re-face of the flavin ring. However, at the si-face of the flavin ring, despite the strict sequence identity, a hydrophobic stretch (residues 47-51, VAAGL) exists in a significantly different conformation compared with both of the independently determined porcine DAO-benzoate structures. This suggests that a context-dependent conformational variability of the hydrophobic stretch accounts for the low affinity for FAD as well as the slower rate of flavin reduction, thus highlighting the unique features of the human enzyme. |
| DOI | 10.1110/ps.062421606 |
| ISSN | 0961-8368 |