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| - | [[Image:1ojb.gif|left|200px]]<br /><applet load="1ojb" size="350" color="white" frame="true" align="right" spinBox="true" | + | #REDIRECT [[2xfu]] This PDB entry is obsolete and replaced by 2xfu |
| - | caption="1ojb, resolution 2.20Å" />
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| - | '''HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH TRANYLCYPROMINE'''<br />
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| - | ==Overview==
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| - | 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.
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| - | ==About this Structure==
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| - | 1OJB is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=FAD:'>FAD</scene> and <scene name='pdbligand=1LP:'>1LP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Amine_oxidase_(flavin-containing) Amine oxidase (flavin-containing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.3.4 1.4.3.4] Known structural/functional Site: <scene name='pdbsite=AC1:1lp+Binding+Site+For+Chain+B'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OJB OCA].
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| - | ==Reference==
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| - | Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures., Binda C, Li M, Hubalek F, Restelli N, Edmondson DE, Mattevi A, Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9750-5. Epub 2003 Aug 11. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12913124 12913124]
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| - | [[Category: Amine oxidase (flavin-containing)]]
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| - | [[Category: Homo sapiens]]
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| - | [[Category: Single protein]]
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| - | [[Category: Binda, C.]]
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| - | [[Category: Edmondson, D E.]]
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| - | [[Category: Mattevi, A.]]
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| - | [[Category: 1LP]]
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| - | [[Category: FAD]]
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| - | [[Category: fad-containing amine oxidase]]
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| - | [[Category: maob]]
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| - | [[Category: oxidoreductase]]
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| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:18:23 2008''
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