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

Claudia Binda, Frantisek Hubálek, Min Li, Yaacov Herzig, Jeffrey Sterling, Dale E. Edmondson, Andrea Mattevi

Research output: Contribution to journalArticlepeer-review

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 Å. 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.

Original languageEnglish (US)
Pages (from-to)1767-1774
Number of pages8
JournalJournal of medicinal chemistry
Volume47
Issue number7
DOIs
StatePublished - Mar 25 2004

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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