1W1H

Crystal Structure of the PDK1 Pleckstrin Homology (PH) domain

Summary for 1W1H

• Entry DOI: 10.2210/pdb1w1h/pdb
• Related: 1H1W 1OKY 1OKZ 1UU3 1UU7 1UU8 1UU9 1UVR 1W1D 1W1G
• Descriptor: 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1, GLYCEROL, SULFATE ION, ... (4 entities in total)
• Functional Keywords: pdk1, phosphoinositide dependent protein kinase 1, pkb, pleckstrin homology domain, inositol phosphate, phosphoinositide, signal transduction, pi3-kinase serine/threonine protein kinase, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: O15530
• Total number of polymer chains: 4
• Total formula weight: 72593.75

Authors

Komander, D.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2004-06-21, release date: 2004-11-19, Last modification date: 2024-05-08)

Primary citation

Komander, D.,Fairservice, A.,Deak, M.,Kular, G.S.,Prescott, A.R.,Downes, C.P.,Safrany, S.T.,Alessi, D.R.,Van Aalten, D.M.F.
Structural Insights Into the Regulation of Pdk1 by Phosphoinositides and Inositol Phosphates
Embo J., 23:3918-, 2004

PubMed Abstract: 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.

PubMed: 15457207
DOI: 10.1038/SJ.EMBOJ.7600379

Experimental method

X-RAY DIFFRACTION (1.45 Å)