2UZR

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer (AKT1-PH_E17K)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

Carpten, J.D.Faber, A.L.Horn, C.Donoho, G.P.Briggs, S.L.Robbins, C.M.Hostetter, G.Boguslawski, S.Moses, T.Y.Savage, S.Uhlik, M.Lin, A.Du, J.Qian, Y.W.Zeckner, D.J.Tucker-Kellogg, G.Touchman, J.Patel, K.Mousses, S.Bittner, M.Schevitz, R.Lai, M.H.Blanchard, K.L.Thomas, J.E.

(2007) Nature 448: 439-444

  • DOI: https://doi.org/10.1038/nature05933
  • Primary Citation of Related Structures:  
    2UZR, 2UZS

  • PubMed Abstract: 

    Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.


  • Organizational Affiliation

    Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RAC-alpha serine/threonine-protein kinase124Homo sapiensMutation(s): 1 
Gene Names: AKT1PKBRAC
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P31749 (Homo sapiens)
Explore P31749 
Go to UniProtKB:  P31749
PHAROS:  P31749
GTEx:  ENSG00000142208 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31749
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.239 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.886α = 90
b = 32.811β = 119.11
c = 42.16γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-07-17
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-09-19
    Changes: Data collection, Database references, Source and taxonomy, Structure summary
  • Version 1.4: 2019-10-16
    Changes: Data collection, Experimental preparation, Other
  • Version 1.5: 2023-12-13
    Changes: Data collection, Database references, Refinement description