1ojc
From Proteopedia
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==Overview== | ==Overview== | ||
| - | 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 ... | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1OJC is a | + | 1OJC 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 FAD as [http://en.wikipedia.org/wiki/ligand ligand]. 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] Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OJC OCA]. |
==Reference== | ==Reference== | ||
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[[Category: oxidoreductase]] | [[Category: oxidoreductase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 13:58:01 2007'' |
Revision as of 11:52, 5 November 2007
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HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH N-(2-AMINOETHYL)-P-CHLOROBENZAMIDE
Overview
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.
About this Structure
1OJC is a Single protein structure of sequence from Homo sapiens with FAD as ligand. Active as Amine oxidase (flavin-containing), with EC number 1.4.3.4 Structure known Active Site: AC1. Full crystallographic information is available from OCA.
Reference
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:12913124
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