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PDBsum entry 2bk3
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Oxidoreductase
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PDB id
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2bk3
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References listed in PDB file
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Key reference
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Title
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Demonstration of isoleucine 199 as a structural determinant for the selective inhibition of human monoamine oxidase b by specific reversible inhibitors.
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Authors
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F.Hubálek,
C.Binda,
A.Khalil,
M.Li,
A.Mattevi,
N.Castagnoli,
D.E.Edmondson.
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Ref.
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J Biol Chem, 2005,
280,
15761-15766.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
FIG. 1. Schematic representation of the MAO B subunit in
complex with trans,trans-farnesol. The FAD-binding domain is in
blue, the substrate-binding domain in red, and the
membrane-binding C-terminal region in green. The FAD cofactor
and trans,trans-farnesol are shown as yellow and black
ball-and-stick representations, respectively. The
inhibitor-binding cavity is outlined by a cyan semitransparent
surface.
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Figure 2.
FIG. 2. Stereo plots of the complex between
trans,trans-farnesol and wild-type MAO B. A, active site
structure of the bound inhibitor and the conformation of
Ile-199. B, close-up view of the position of bound
trans,trans-farnesol with respect to the flavin ring. The dashed
lines refer to the distances (3.4 Å) between the farnesol
oxygen and the flavin C(4a) position and between the C(1) of
farnesol and the flavin N(5) position.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
15761-15766)
copyright 2005.
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