1O6L

Crystal structure of an activated Akt/protein kinase B (PKB-PIF chimera) ternary complex with AMP-PNP and GSK3 peptide

Summary for 1O6L

• Entry DOI: 10.2210/pdb1o6l/pdb
• Related: 1GZK 1GZN 1GZO 1O6K
• Descriptor: RAC-BETA SERINE/THREONINE PROTEIN KINASE, GLYCOGEN SYNTHASE KINASE-3 BETA, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: protein kinase, transferase, serine/threonine-protein kinase
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm: P49841
• Total number of polymer chains: 2
• Total formula weight: 41128.15

Authors

Yang, J.,Cron, P.,Good, V.M.,Thompson, V.,Hemmings, B.A.,Barford, D. (deposition date: 2002-10-08, release date: 2002-11-19, Last modification date: 2024-05-01)

Primary citation

Yang, J.,Cron, P.,Good, V.M.,Thompson, V.,Hemmings, B.A.,Barford, D.
Crystal Structure of an Activated Akt/Protein Kinase B Ternary Complex with Gsk-3 Peptide and AMP-Pnp
Nat.Struct.Biol., 9:940-, 2002

PubMed Abstract: The protein kinase Akt/PKB is stimulated by the phosphorylation of two regulatory residues, Thr 309 of the activation segment and Ser 474 of the hydrophobic motif (HM), that are structurally and functionally conserved within the AGC kinase family. To understand the mechanism of PKB regulation, we determined the crystal structures of activated kinase domains of PKB in complex with a GSK3beta-peptide substrate and an ATP analog. The activated state of the kinase was generated by phosphorylating Thr 309 using PDK1 and mimicking Ser 474 phosphorylation either with the S474D substitution or by replacing the HM of PKB with that of PIFtide, a potent mimic of a phosphorylated HM. Comparison with the inactive PKB structure indicates that the role of Ser 474 phosphorylation is to promote the engagement of the HM with the N-lobe of the kinase domain, promoting a disorder-to-order transition of the alphaC helix. The alphaC helix, by interacting with pThr 309, restructures and orders the activation segment, generating an active kinase conformation. Analysis of the interactions between PKB and the GSK3beta-peptide explains how PKB selects for protein substrates distinct from those of PKA.

PubMed: 12434148
DOI: 10.1038/NSB870

Experimental method

X-RAY DIFFRACTION (1.6 Å)