1S3E

Crystal structure of MAOB in complex with 6-hydroxy-N-propargyl-1(R)-aminoindan

Summary for 1S3E

• Entry DOI: 10.2210/pdb1s3e/pdb
• Related: 1S2Q 1S2Y 1S3B
• Descriptor: Amine oxidase [flavin-containing] B, FLAVIN-ADENINE DINUCLEOTIDE, (3R)-3-(PROP-2-YNYLAMINO)INDAN-5-OL, ... (4 entities in total)
• Functional Keywords: human monoamine oxidase, inhibitor binding, rasagiline, enantioselectivity, flavin, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion outer membrane; Single-pass type IV membrane protein; Cytoplasmic side: P27338
• Total number of polymer chains: 2
• Total formula weight: 119621.04

Authors

Binda, C.,Hubalek, F.,Li, M.,Herzig, Y.,Sterling, J.,Edmondson, D.E.,Mattevi, A. (deposition date: 2004-01-13, release date: 2004-03-30, Last modification date: 2011-07-13)

Primary citation

Binda, C.,Li, M.,Herzig, Y.,Sterling, J.,Edmondson, D.E.,Mattevi, A.
Crystal Structures of Monoamine Oxidase B in Complex with Four Inhibitors of the N-Propargylaminoindan Class.
J.Med.Chem., 47:1767-1774, 2004

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.

PubMed: 15027868
DOI: 10.1021/jm031087c

Experimental method

X-RAY DIFFRACTION (1.6 Å)