2bk4
From Proteopedia
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'''HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH RASAGILINE''' | '''HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH RASAGILINE''' | ||
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==Reference== | ==Reference== | ||
Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors., Hubalek F, Binda C, Khalil A, Li M, Mattevi A, Castagnoli N, Edmondson DE, J Biol Chem. 2005 Apr 22;280(16):15761-6. Epub 2005 Feb 14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15710600 15710600] | Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors., Hubalek F, Binda C, Khalil A, Li M, Mattevi A, Castagnoli N, Edmondson DE, J Biol Chem. 2005 Apr 22;280(16):15761-6. Epub 2005 Feb 14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15710600 15710600] | ||
| - | [[Category: Amine oxidase (flavin-containing)]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: Li, M.]] | [[Category: Li, M.]] | ||
[[Category: Mattevi, A.]] | [[Category: Mattevi, A.]] | ||
| - | [[Category: | + | [[Category: Fad]] |
| - | [[Category: | + | [[Category: Fad-containing amine oxidase]] |
| - | [[Category: | + | [[Category: Flavoprotein]] |
| - | [[Category: | + | [[Category: Maob]] |
| - | [[Category: | + | [[Category: Maob acetylation]] |
| - | [[Category: | + | [[Category: Oxidoreductase]] |
| - | [[Category: | + | [[Category: Transmembrane]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 20:24:00 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 17:24, 3 May 2008
HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH RASAGILINE
Overview
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.
About this Structure
2BK4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase B by specific reversible inhibitors., Hubalek F, Binda C, Khalil A, Li M, Mattevi A, Castagnoli N, Edmondson DE, J Biol Chem. 2005 Apr 22;280(16):15761-6. Epub 2005 Feb 14. PMID:15710600 Page seeded by OCA on Sat May 3 20:24:00 2008
