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Title
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High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site.
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Authors
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R.M.Biondi,
D.Komander,
C.C.Thomas,
J.M.Lizcano,
M.Deak,
D.R.Alessi,
D.M.van Aalten.
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Ref.
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EMBO J, 2002,
21,
4219-4228.
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PubMed id
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Abstract
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3-phosphoinositide dependent protein kinase-1 (PDK1) plays a key role in
regulating signalling pathways by activating AGC kinases such as PKB/Akt and
S6K. Here we describe the 2.0 A crystal structure of the PDK1 kinase domain in
complex with ATP. The structure defines the hydrophobic pocket termed the
"PIF-pocket", which plays a key role in mediating the interaction and
phosphorylation of certain substrates such as S6K1. Phosphorylation of S6K1 at
its C-terminal PIF-pocket-interacting motif promotes the binding of S6K1 with
PDK1. In the PDK1 structure, this pocket is occupied by a crystallographic
contact with another molecule of PDK1. Interestingly, close to the PIF-pocket in
PDK1, there is an ordered sulfate ion, interacting tightly with four surrounding
side chains. The roles of these residues were investigated through a combination
of site-directed mutagenesis and kinetic studies, the results of which confirm
that this region of PDK1 represents a phosphate-dependent docking site. We
discuss the possibility that an analogous phosphate-binding regulatory motif may
participate in the activation of other AGC kinases. Furthermore, the structure
of PDK1 provides a scaffold for the design of specific PDK1 inhibitors.
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