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PDBsum entry 2q8h
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References listed in PDB file
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Key reference
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Title
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Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by azd7545, Dichloroacetate, And radicicol.
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Authors
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M.Kato,
J.Li,
J.L.Chuang,
D.T.Chuang.
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Ref.
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Structure, 2007,
15,
992.
[DOI no: ]
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PubMed id
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Abstract
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Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that
downregulate the pyruvate dehydrogenase complex (PDC) by reversible
phosphorylation in mitochondria. We have determined structures of human PDK1 or
PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We
show that the trifluoromethylpropanamide end of AZD7545 projects into the
lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1
and PDK3 activities by aborting kinase binding to the PDC scaffold.
Paradoxically, AZD7545 at saturating concentrations robustly increases
scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA
density is present in the helix bundle in the N-terminal domain of PDK1. Bound
DCA promotes local conformational changes that are communicated to both
nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the
inactivation of kinase activity. Finally, radicicol inhibits kinase activity by
binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI
from the same ATPase/kinase superfamily.
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Figure 1.
Figure 1.
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Figure 6.
Figure 6. Structure of the Radicicol-Binding Site in PDK3-L2
(A) The omit electron density map of radicicol bound to
PDK3. The density is superimposed on the refined model of
radicicol at the 3σ level in blue and the 9σ level in red.
(B) Interactions between PDK3 residues and radicicol. H
bonds are indicated by dashed lines. Water molecules are
depicted as red balls.
(C) Comparison between radicicol and
ATP bound to PDK3. The structure of PDK3-L2-ATP (PDB ID code
1Y8P; Kato et al., 2005) (magenta) is superimposed on
PDK3-L2-radicicol (cyan).
(D) Superimposition of radicicol
molecules bound to PDK1 (cyan), Hsp90 (PDB ID code 1BGQ; Roe et
al., 1999) (pink), and Topo VI (PDB ID code 2HKJ; Corbett and
Berger, 2005) (yellow). The three structures were superimposed
based on the corresponding residues shown in the figure. Stereo
figures of (B)–(D) are provided in Figure S4.
(E)
Comparison of the shape of the radicicol-binding pockets of
PDK3, Hsp90, and Topo VI. The electrostatic surface of each
protein is shown with the negative charge in red and the
positive charge in blue.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2007,
15,
992-0)
copyright 2007.
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