Summary
PDB 1W1G deposited: 2004-06-21 modified: 2009-02-24
Title CRYSTAL STRUCTURE OF THE PDK1 PLECKSTRIN HOMOLOGY (PH) DOMAIN BOUND TO DIC4-PHOSPHATIDYLINOSITOL (3,4,5)-TRISPHOSPHATE
Authors Alessi, D.R., Deak, M., Downes, C.P., Fairservice, A., Komander, D., Kular, G.S., Prescott, A.R., Safrany, S.T., Van Aalten, D.M.F.
Method X-RAY DIFFRACTION
Structure factors resolution 1.45 rfactor 0.182 rfree 0.236
DPI 0.18 theoretical min: 0.08
Related PDB Entries 1W1D 1W1H
Citations

3-phosphoinositide-dependent protein kinase-1 (PDK1) phosphorylates and activates many kinases belonging to the AGC subfamily. PDK1 possesses a C-terminal pleckstrin homology (PH) domain that interacts with PtdIns(3,4,5)P3/PtdIns(3,4)P2 and with lower affinity to PtdIns(4,5)P2. We describe the crystal structure of the PDK1 PH domain, in the absence and presence of PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4. The structures reveal a 'budded' PH domain fold, possessing an N-terminal extension forming an integral part of the overall fold, and display an unusually spacious ligand-binding site. Mutagenesis and lipid-binding studies were used to define the contribution of residues involved in phosphoinositide binding. Using a novel quantitative binding assay, we found that Ins(1,3,4,5,6)P5 and InsP6, which are present at micromolar levels in the cytosol, interact with full-length PDK1 with nanomolar affinities. Utilising the isolated PDK1 PH domain, which has reduced affinity for Ins(1,3,4,5,6)P5/InsP6, we perform localisation studies that suggest that these inositol phosphates serve to anchor a portion of cellular PDK1 in the cytosol, where it could activate its substrates such as p70 S6-kinase and p90 ribosomal S6 kinase that do not interact with phosphoinositides.

Embo J. 2004 Oct; 23(20):3918- doi:10.1038/SJ.EMBOJ.7600379

Cross References
Database source Identifier Description
PubMed 15457207 EMJODG
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
1W1G/0 1W1G 0 monomer 0 1 1 1329