1H1W

High resolution crystal structure of the human PDK1 catalytic domain

Summary for 1H1W

• Entry DOI: 10.2210/pdb1h1w/pdb
• Descriptor: 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: transferase, phosphoinositide dependent protein kinase, pka, agc kinase activation, pif-pocket, pi3-kinase signalling, serine/threonine-protein kinase, atp-binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 1
• Total formula weight: 35176.72

Authors

Biondi, R.M.,Komander, D.,Thomas, C.C.,Lizcano, J.M.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2002-07-23, release date: 2003-07-17, Last modification date: 2024-11-13)

Primary citation

Biondi, R.M.,Komander, D.,Thomas, C.C.,Lizcano, J.M.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F.
High Resolution Crystal Structure of the Human Pdk1 Catalytic Domain Defines the Regulatory Phosphopeptide Docking Site
Embo J., 21:4219-, 2003

PubMed Abstract: 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.

PubMed: 12169624
DOI: 10.1093/EMBOJ/CDF437

Experimental method

X-RAY DIFFRACTION (2 Å)