Crystal Structures of Monoamine Oxidase B in Complex with Four Inhibitors of theN-Propargylaminoindan Class

• DOI: 10.1021/jm031087c
• Publication Date: 2004-03-18T05:37:44Z
• Authors: Claudia Binda; Frantisek Hubálek; Min Li; Yaacov Herzig; Jeffrey Sterling; Dale E. Edmondson; Andrea Mattevi
• Keywords: Rasagiline; Propargyl; Monoamine oxidase B

Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures MAO in complex with four N-propargylaminoindan class covalent inhibitors (rasagiline, N-propargyl-1(S)-aminoindan, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan) have been determined at a resolution better than 2.1 Å. Rasagiline, N-methyl-N-propargyl-1(R)-aminoindan adopt essentially same conformation extended propargyl chain covalently bound to flavin indan ring located rear substrate cavity. N-Propargyl-1(S)-aminoindan binds flipped respect other inhibitors, which causes slight movement Tyr326 side chain. Four ordered water molecules are integral part active site establish H-bond interactions inhibitor atoms. These structural studies may guide future drug design improve selectivity efficacy by introducing appropriate substituents on rasagiline molecular scaffold.