title: Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class.
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.
authors.affiliation: Department of Genetics and Microbiology, University of Pavia, Via Abbiategrasso 207, Pavia, 27100 Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.forename: Frantisek
authors.initials: F
authors.lastname: Hubálek
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Herzig
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sterling
authors.forename: Dale E
authors.initials: DE
authors.lastname: Edmondson
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D007189:Indans / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D007189:Indans; D008996:Monoamine Oxidase Inhibitors; C031967:rasagiline; D008995:Monoamine Oxidase