1OJ9

HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH 1,4-DIPHENYL-2-BUTENE

Summary for 1OJ9

• Entry DOI: 10.2210/pdb1oj9/pdb
• Related: 1GOS 1H8R 1OJA 1OJB 1OJC 1OJD
• Descriptor: AMINE OXIDASE [FLAVIN-CONTAINING] B, FLAVIN-ADENINE DINUCLEOTIDE, 1,4-DIPHENYL-2-BUTENE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, fad-containing amine oxidase, maob
• 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: 119663.16

Authors

Binda, C.,Edmondson, D.E.,Mattevi, A. (deposition date: 2003-07-08, release date: 2003-08-15, Last modification date: 2024-10-23)

Primary citation

Binda, C.,Li, M.,Hubalek, F.,Restelli, N.,Edmondson, D.E.,Mattevi, A.
Insights Into the Mode of Inhibition of Human Mitochondrial Monoamine Oxidase B from High-Resolution Crystal Structures
Proc.Natl.Acad.Sci.USA, 100:9750-, 2003

PubMed Abstract: Monoamine oxidase B (MAO-B) is an outer mitochondrial membrane-bound enzyme that catalyzes the oxidative deamination of arylalkylamine neurotransmitters and has been a target for a number of clinically used drug inhibitors. The 1.7-A structure of the reversible isatin-MAO-B complex has been determined; it forms a basis for the interpretation of the enzyme's structure when bound to either reversible or irreversible inhibitors. 1,4-Diphenyl-2-butene is found to be a reversible MAO-B inhibitor, which occupies both the entrance and substrate cavity space in the enzyme. Comparison of these two structures identifies Ile-199 as a "gate" between the two cavities. Rotation of the side chain allows for either separation or fusion of the two cavities. Inhibition of the enzyme with N-(2-aminoethyl)-p-chlorobenzamide results in the formation of a covalent N(5) flavin adduct with the phenyl ring of the inhibitor occupying a position in the catalytic site overlapping that of isatin. Inhibition of MAO-B with the clinically used trans-2-phenylcyclopropylamine results in the formation of a covalent C(4a) flavin adduct with an opened cyclopropyl ring and the phenyl ring in a parallel orientation to the flavin. The peptide bond between the flavin-substituted Cys-397 and Tyr-398 is in a cis conformation, which allows the proper orientation of the phenolic ring of Tyr-398 in the active site. The flavin ring exists in a twisted nonplanar conformation, which is observed in the oxidized form as well as in both the N(5) and the C(4a) adducts. An immobile water molecule is H-bonded to Lys-296 and to the N(5) of the flavin as observed in other flavin-dependent amine oxidases. The active site cavities are highly apolar; however, hydrophilic areas exist near the flavin and direct the amine moiety of the substrate for binding and catalysis. Small conformational changes are observed on comparison of the different inhibitor-enzyme complexes. Future MAO-B drug design will need to consider "induced fit" contributions as an element in ligand-enzyme interactions.

PubMed: 12913124
DOI: 10.1073/PNAS.1633804100

Experimental method

X-RAY DIFFRACTION (2.3 Å)