2BK3

Human Monoamine Oxidase B in complex with Farnesol

Summary for 2BK3

• Entry DOI: 10.2210/pdb2bk3/pdb
• Related: 1GOS 1H8R 1OJ9 1OJA 1OJB 1OJC 1OJD 1S2Q 1S2Y 1S3B 1S3E 2BK4 2BK5
• Descriptor: AMINE OXIDASE [FLAVIN-CONTAINING] B, FLAVIN-ADENINE DINUCLEOTIDE, (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol, ... (4 entities in total)
• Functional Keywords: acetylation, farnesol, fad, fad-containing amine oxidase, flavoprotein, maob, mitochondrion, oxidoreductase, transmembrane
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 119691.29

Authors

Binda, C.,Edmondson, D.E.,Mattevi, A. (deposition date: 2005-02-10, release date: 2005-02-14, Last modification date: 2024-11-13)

Primary citation

Hubalek, F.,Binda, C.,Khalil, A.,Li, M.,Mattevi, A.,Castagnoli, N.,Edmondson, D.E.
Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors.
J. Biol. Chem., 280:15761-15766, 2005

PubMed Abstract: Several reversible inhibitors selective for human monoamine oxidase B (MAO B) that do not inhibit MAO A have been described in the literature. The following compounds: 8-(3-chlorostyryl)caffeine, 1,4-diphenyl-2-butene, and trans,trans-farnesol are shown to inhibit competitively human, horse, rat, and mouse MAO B with K(i) values in the low micromolar range but are without effect on either bovine or sheep MAO B or human MAO A. In contrast, the reversible competitive inhibitor isatin binds to all known MAO B and MAO A with similar affinities. Sequence alignments and the crystal structures of human MAO B in complex with 1,4-diphenyl-2-butene or with trans,trans-farnesol provide molecular insights into these specificities. These inhibitors span the substrate and entrance cavities with the side chain of Ile-199 rotated out of its normal conformation suggesting that Ile-199 is gating the substrate cavity. Ile-199 is conserved in all known MAO B sequences except bovine MAO B, which has Phe in this position (the sequence of sheep MAO B is unknown). Phe is conserved in the analogous position in MAO A sequences. The human MAO B I199F mutant protein of MAO B binds to isatin (K(i) = 3 microM) but not to the three inhibitors listed above. The crystal structure of this mutant demonstrates that the side chain of Phe-199 interferes with the binding of those compounds. This suggests that the Ile-199 "gate" is a determinant for the specificity of these MAO B inhibitors and provides a molecular basis for the development of MAO B-specific reversible inhibitors without interference with MAO A function in neurotransmitter metabolism.

PubMed: 15710600
DOI: 10.1074/jbc.M500949200

Experimental method

X-RAY DIFFRACTION (1.8 Å)