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PDBsum entry 1ojc
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Oxidoreductase
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PDB id
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1ojc
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Insights into the mode of inhibition of human mitochondrial monoamine oxidase b from high-Resolution crystal structures.
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Authors
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C.Binda,
M.Li,
F.Hubalek,
N.Restelli,
D.E.Edmondson,
A.Mattevi.
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Ref.
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Proc Natl Acad Sci U S A, 2003,
100,
9750-9755.
[DOI no: ]
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PubMed id
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Abstract
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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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Figure 2.
Fig. 2. Structures of MAO-B inhibitors used in this study
and atomic numbering of the flavin ring.
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Figure 4.
Fig. 4. LIGPLOT (15) illustration of 1,4-diphenyl-2-butene
binding to MAO-B. Dashed lines indicate H-bonds. Carbons are in
black, nitrogens in blue, oxygens in red, and sulfurs in yellow.
Water molecules are shown as cyan spheres.
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