2C66

MAO inhibition by rasagiline analogues

2C66 の概要

• エントリーDOI: 10.2210/pdb2c66/pdb
• 関連するPDBエントリー: 1GOS 1H8R 1OJ9 1OJA 1OJB 1OJC 1OJD 1S2Q 1S2Y 1S3B 1S3E 2BK3 2BK4 2BK5 2BYB 2C64 2C65 2C67
• 分子名称: AMINE OXIDASE (FLAVIN-CONTAINING) B, FLAVIN-ADENINE DINUCLEOTIDE, 4-HYDROXY-N-PROPARGYL-1(R)-AMINOINDAN, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, enantioselectivity, fad, flavin, flavoprotein, human monoamine oxidase, inhibitor binding, mitochondrion, rasagiline, transmembrane, parkinson
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Mitochondrion outer membrane; Single-pass type IV membrane protein; Cytoplasmic side: P27338
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 119621.04

構造登録者

Binda, C.,Hubalek, F.,Li, M.,Herzig, Y.,Sterling, J.,Edmondson, D.E.,Mattevi, A. (登録日: 2005-11-07, 公開日: 2006-01-04, 最終更新日: 2024-11-13)

主引用文献

Binda, C.,Hubalek, F.,Li, M.,Herzig, Y.,Sterling, J.,Edmondson, D.E.,Mattevi, A.
Binding of Rasagiline-Related Inhibitors to Human Monoamine Oxidases: A Kinetic and Crystallographic Analysis.
J.Med.Chem., 48:8148-, 2005

PubMed Abstract: Monoamine oxidases A and B (MAO A and B) catalyze the degradation of neurotransmitters and represent drug targets for the treatment of neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective inhibitor that has been approved as a novel anti-Parkinson's drug. In this study, we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues. Different substituents added onto the rasagiline scaffold alter the binding affinity depending on the position on the aminoindan ring and on the size of the substituent. Compounds with a hydroxyl group on either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier substituent such as a carbamate is tolerated only at the C4 position. The 1.7 A crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows that the binding mode is similar to that of rasagiline with the carbamate moiety occupying the entrance cavity space. 1(R)-Aminoindan, the major metabolic product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline.

PubMed: 16366596
DOI: 10.1021/JM0506266

実験手法

X-RAY DIFFRACTION (2.5 Å)