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PDBsum entry 1u7t
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Oxidoreductase
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PDB id
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1u7t
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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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Crystal structure of human abad/hsd10 with a bound inhibitor: implications for design of alzheimer'S disease therapeutics.
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Authors
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C.R.Kissinger,
P.A.Rejto,
L.A.Pelletier,
J.A.Thomson,
R.E.Showalter,
M.A.Abreo,
C.S.Agree,
S.Margosiak,
J.J.Meng,
R.M.Aust,
D.Vanderpool,
B.Li,
A.Tempczyk-Russell,
J.E.Villafranca.
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Ref.
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J Mol Biol, 2004,
342,
943-952.
[DOI no: ]
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PubMed id
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Abstract
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The enzyme 17beta-hydroxysteroid dehydrogenase type 10 (HSD10), also known as
amyloid beta-peptide-binding alcohol dehydrogenase (ABAD), has been implicated
in the development of Alzheimer's disease. This protein, a member of the
short-chain dehydrogenase/reductase family of enzymes, has been shown to bind
beta-amyloid and to participate in beta-amyloid neurotoxicity. We have
determined the crystal structure of human ABAD/HSD10 complexed with NAD(+) and
an inhibitory small molecule. The inhibitor occupies the substrate-binding site
and forms a covalent adduct with the NAD(+) cofactor. The crystal structure
provides a basis for the design of potent, highly specific ABAD/HSD10 inhibitors
with potential application in the treatment of Alzheimer's disease.
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Figure 1.
Figure 1. Structure of the ABAD/HSD10 monomer. (a) Stereo
C^a trace of ABAD/HSD10 monomer. Every tenth residue is
numbered. The bound NAD-inhibitor adduct is shown. (b) Ribbon
diagram of ABAD/HSD10 monomer, with the NAD-inhibitor adduct
shown in ball-and-stick representation. The ribbon is white at
the amino terminus and becomes darker blue moving toward the
carboxy terminus. C^a positions of residues in the insertion
regions of ABAD/HSD10 relative to other SDR enzymes (residues
102-107 and 141-146, see Figure 2) are shown as yellow spheres.
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Figure 3.
Figure 3. Ribbon representation of the ABAD/HSD10 tetramer.
The tetramer is viewed down one of three mutually perpendicular
2-fold axes. Individual monomers are shown in red, green, blue
and yellow. The bound NAD^+ and NAD-inhibitor adduct molecules
are shown in ball-and-stick representation.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
342,
943-952)
copyright 2004.
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