Download MendeleyCrystal Structures of Monoamine Oxidase B in Complex with Four Inhibitors of the N-Propargylaminoindan Class.
Binda, C., Li, M., Herzig, Y., Sterling, J., Edmondson, D.E., Mattevi, A.(2004) J Med Chem 47: 1767-1774
- PubMed: 15027868
- DOI: https://doi.org/10.1021/jm031087c
- Primary Citation of Related Structures:
1S2Q, 1S2Y, 1S3B, 1S3E - PubMed Abstract:
Monoamine oxidase B (MAO B) is an outer mitochondrial membrane enzyme that catalyzes the oxidation of arylalkylamine neurotransmitters. The crystal structures of MAO B in complex with four of the N-propargylaminoindan class of MAO 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 of better than 2.1 A. Rasagiline, 6-hydroxy-N-propargyl-1(R)-aminoindan, and N-methyl-N-propargyl-1(R)-aminoindan adopt essentially the same conformation with the extended propargyl chain covalently bound to the flavin and the indan ring located in the rear of the substrate cavity. N-Propargyl-1(S)-aminoindan binds with the indan ring in a flipped conformation with respect to the other inhibitors, which causes a slight movement of the Tyr326 side chain. Four ordered water molecules are an integral part of the active site and establish H-bond interactions to the inhibitor atoms. These structural studies may guide future drug design to improve selectivity and efficacy by introducing appropriate substituents on the rasagiline molecular scaffold.
Organizational Affiliation:
Department of Genetics and Microbiology, University of Pavia, Via Abbiategrasso 207, Pavia, 27100 Italy.
