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| - | [[Image:2bk5.gif|left|200px]] | + | {{Seed}} |
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| | {{STRUCTURE_2bk5| PDB=2bk5 | SCENE= }} | | {{STRUCTURE_2bk5| PDB=2bk5 | SCENE= }} |
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| - | '''HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH ISATIN'''
| + | ===HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH ISATIN=== |
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| - | ==Overview==
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| - | 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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_15710600}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 15710600 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_15710600}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Oxidoreductase]] | | [[Category: Oxidoreductase]] |
| | [[Category: Transmembrane]] | | [[Category: Transmembrane]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 20:23:58 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 20:13:12 2008'' |
Revision as of 17:13, 27 July 2008
Template:STRUCTURE 2bk5
HUMAN MONOAMINE OXIDASE B: I199F MUTANT IN COMPLEX WITH ISATIN
Template:ABSTRACT PUBMED 15710600
About this Structure
2BK5 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
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