Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders.
Monoamine oxidase B (MAO B) is a mitochondrial outermembrane flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. We determined the structure of the human enzyme to 3 A resolution. The enzyme binds to the membrane through a C-terminal transmembrane helix and apolar loops located at various positions in the sequence. The electron density shows that pargyline, an analog of the clinically used MAO B inhibitor, deprenyl, binds covalently to the flavin N5 atom. The active site of MAO B consists of a 420 A(3)-hydrophobic substrate cavity interconnected to an entrance cavity of 290 A(3). The recognition site for the substrate amino group is an aromatic cage formed by Tyr 398 and Tyr 435. The structure provides a framework for probing the catalytic mechanism, understanding the differences between the B- and A-monoamine oxidase isoforms and designing specific inhibitors.
Binda
Claudia
C
Department of Genetics and Microbiology, University of Pavia, Pavia, Italy.
Newton-Vinson
Paige
P
Hubálek
Frantisek
F
Edmondson
Dale E
DE
Mattevi
Andrea
A
D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism; D009422:Nervous System Diseases / Q000188:drug therapy / Q000201:enzymology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase