PDBsum entry 2uzr

Transferase

PDB id: 2uzr

Contents

Protein chain

113 a.a. *

Waters ×40

* Residue conservation analysis

PDB id:

2uzr

Name:

Transferase

Title:

A transforming mutation in the pleckstrin homology domain of akt1 in cancer (akt1-ph_e17k)

Structure:

Rac-alpha serine/threonine-protein kinase. Chain: a. Fragment: residues 1-123. Synonym: protein kinase b,pkb,protein kinase b alpha,pkb alpha,proto- oncogenE C-akt,rac-pk-alpha. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: akt1, pkb, rac. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek293t

Resolution:

1.94Å R-factor: 0.239 R-free: 0.257

Authors:

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

Key ref:

J.D.Carpten et al. (2007). A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature, 448, 439-444. PubMed id: 17611497 DOI: 10.1038/nature05933

Date:

01-May-07 Release date: 17-Jul-07

Protein chain

P31749  (AKT1_HUMAN) -  RAC-alpha serine/threonine-protein kinase from Homo sapiens

Seq: 480 a.a.

Struc: 113 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nature05933

Nature 448:439-444 (2007)

PubMed id: 17611497

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

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

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.

Selected figure(s)

Figure 1.
Figure 1: Lys 17 alters the apo and Ins(1,3,4,5)P[4]-complexed AKT1 PHD structure. a, In apo wild-type PHD, an ionic interaction between Glu 17 and Lys 14 (line) fills the binding pocket. b, E17K PHD apo with Lys 17 turned away from Lys 14. c, E17K PHD with Lys 17 involved in new hydrogen bonds (dashed lines) with a water molecule (orange sphere), interposed with the D6-hydroxyl group, and the D5-phosphate of Ins(1,3,4,5)P[4] (orange). Lys 17 also forms a new hydrogen bond with the hydroxyl of Tyr 18. The D1-phosphate forms a hydrogen bond with the amide of Tyr 18, similar to the wild-type PHD. Distances shown are in angstroms.

Figure 5.
Figure 5: Timing and signature of AKT1(E17K)-driven leukaemia. a, Timing of leukaemia onset as determined by the appearance of discernible P-AKT(Ser 473)–GFP cells in blood of rescued lethally irradiated host animals. Myr–AKT1 (n = 12, solid circles), AKT1(E17K) (n = 10, filled triangles), AKT1(WT) (n = 10, open squares) and mock transduction (n = 3, X) is shown. b, Representative flow cytometry results from leukaemic mice (AKT1(E17K) and Myr–AKT1) and non-leukaemic mice (Mock and AKT1(WT)) after staining for P-AKT(Ser 473). c, Stained blood smear from a representative AKT1(E17K) animal showing leukaemic blasts ( 100 magnification).

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 448, 439-444) copyright 2007.

Figures were selected by the author.