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1ojb
From Proteopedia
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[[Image:1ojb.gif|left|200px]] | [[Image:1ojb.gif|left|200px]] | ||
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'''HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH TRANYLCYPROMINE''' | '''HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH TRANYLCYPROMINE''' | ||
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==Reference== | ==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:[http://www.ncbi.nlm.nih.gov/pubmed/12913124 12913124] | 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://www.ncbi.nlm.nih.gov/pubmed/12913124 12913124] | ||
| - | [[Category: Amine oxidase (flavin-containing)]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: Edmondson, D E.]] | [[Category: Edmondson, D E.]] | ||
[[Category: Mattevi, A.]] | [[Category: Mattevi, A.]] | ||
| - | [[Category: | + | [[Category: Fad-containing amine oxidase]] |
| - | [[Category: | + | [[Category: Maob]] |
| - | [[Category: | + | [[Category: Oxidoreductase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 03:55:12 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 00:55, 3 May 2008
HUMAN MONOAMINE OXIDASE B IN COMPLEX WITH TRANYLCYPROMINE
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
1OJB is a Single protein structure of sequence from Homo sapiens. 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 Page seeded by OCA on Sat May 3 03:55:12 2008
