Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP.
Nat Struct Biol
; 9(12): 940-4, 2002 Dec.
Article
in En
| MEDLINE
| ID: mdl-12434148
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Models, Molecular
/
Adenylyl Imidodiphosphate
/
Proto-Oncogene Proteins
/
Protein Serine-Threonine Kinases
/
Glycogen Synthase Kinase 3
Limits:
Animals
Language:
En
Journal:
Nat Struct Biol
Journal subject:
BIOLOGIA MOLECULAR
Year:
2002
Document type:
Article
Affiliation country:
United kingdom
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA