1H10

HIGH RESOLUTION STRUCTURE OF THE PLECKSTRIN HOMOLOGY DOMAIN OF PROTEIN KINASE B/AKT BOUND TO INS(1,3,4,5)-TETRAKISPHOPHATE

Summary for 1H10

• Entry DOI: 10.2210/pdb1h10/pdb
• Descriptor: RAC-ALPHA SERINE/THREONINE KINASE, INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE (3 entities in total)
• Functional Keywords: transferase, signalling protein, phosphoinositides, protein kinase b, pleckstrin, inositol tetrakisphophate, phosphorylation, serine/threonine protein kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 15440.47

Authors

Thomas, C.C.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2002-07-01, release date: 2003-06-27, Last modification date: 2024-10-23)

Primary citation

Thomas, C.C.,Deak, M.,Alessi, D.R.,Van Aalten, D.M.F.
High Resolution Structure of the Pleckstrin Homology Domain of Protein Kinase B/Akt Bound to Phosphatidylinositol (3,4,5)-Trisphosphate
Curr.Biol., 12:1256-, 2002

PubMed Abstract: The products of PI 3-kinase activation, PtdIns(3,4,5)P3 and its immediate breakdown product PtdIns(3,4)P2, trigger physiological processes, by interacting with proteins possessing pleckstrin homology (PH) domains. One of the best characterized PtdIns(3,4,5)P3/PtdIns(3,4)P2 effector proteins is protein kinase B (PKB), also known as Akt. PKB possesses a PH domain located at its N terminus, and this domain binds specifically to PtdIns(3,4,5)P3 and PtdIns(3,4)P2 with similar affinity. Following activation of PI 3-kinase, PKB is recruited to the plasma membrane by virtue of its interaction with PtdIns(3,4,5)P3/PtdIns(3,4)P2. PKB is then activated by the 3-phosphoinositide-dependent pro-tein kinase-1 (PDK1), which like PKB, possesses a PtdIns(3,4,5)P3/PtdIns(3,4)P2 binding PH domain. Here, we describe the high-resolution crystal structure of the isolated PH domain of PKB(alpha) in complex with the head group of PtdIns(3,4,5)P3. The head group has a significantly different orientation and location compared to other Ins(1,3,4,5)P4 binding PH domains. Mutagenesis of the basic residues that form ionic interactions with the D3 and D4 phosphate groups reduces or abolishes the ability of PKB to interact with PtdIns(3,4,5)P3 and PtdIns(3,4)P2. The D5 phosphate faces the solvent and forms no significant interactions with any residue on the PH domain, and this explains why PKB interacts with similar affinity with both PtdIns(3,4,5)P3 and PtdIns(3,4)P2.

PubMed: 12176338
DOI: 10.1016/S0960-9822(02)00972-7

Experimental method

X-RAY DIFFRACTION (1.4 Å)