Summary
PDB 1W1H deposited: 2004-06-21 modified: 2009-02-24
Title CRYSTAL STRUCTURE OF THE PDK1 PLECKSTRIN HOMOLOGY (PH) DOMAIN
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 0.156 rfree 0.206
DPI 0.16 theoretical min: 0.07
Related PDB Entries 1W1D 1W1G
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
1W1H/1 1W1H 1 monomer 0 1 4 1346
1W1H/2 1W1H 2 monomer 0 1 5 1401
1W1H/3 1W1H 3 monomer 0 1 3 1292
1W1H/4 1W1H 4 monomer 0 1 2 1200