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PDBsum entry 1w2x
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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 the carboxyltransferase domain of acetyl-Coenzyme a carboxylase in complex with cp-640186.
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Authors
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H.Zhang,
B.Tweel,
J.Li,
L.Tong.
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Ref.
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Structure, 2004,
12,
1683-1691.
[DOI no: ]
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PubMed id
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Abstract
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Acetyl-coenzyme A carboxylases (ACCs) are important targets for the development
of therapeutic agents against obesity, diabetes, and other diseases. CP-640186
is a potent inhibitor of mammalian ACCs and can reduce body weight and improve
insulin sensitivity in test animals. It is believed to target the
carboxyltransferase (CT) domain of these enzymes. Here we report the crystal
structure of the yeast CT domain in complex with CP-640186. The inhibitor is
bound in the active site at the interface of a dimer of the CT domain. CP-640186
has tight interactions with the putative biotin binding site in the CT domain
and demonstrates a distinct mode of inhibiting the CT activity as compared to
the herbicides that inhibit plant ACCs. The affinity of inhibitors for the CT
domain has been assessed using kinetic and fluorescence anisotropy binding
studies. The structural information identifies three regions for drug binding in
the active site of CT.
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Figure 4.
Figure 4. Three Distinct Binding Regions in the Active Site
of CT(A) Molecular surface of the active site region of yeast
CT. The CoA and CP-640186 molecules are shown in gray and gold,
respectively. This panel was produced with Grasp (Nicholls et
al., 1991).(B) Comparison of the binding modes of CP-640186 (in
gold), haloxyfop (black), and CoA (gray). This panel was
produced with Ribbons (Carson, 1987).
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2004,
12,
1683-1691)
copyright 2004.
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