2UZS

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

Summary for 2UZS

• Entry DOI: 10.2210/pdb2uzs/pdb
• Related: 1H10 1UNP 1UNQ 1UNR 2UVM 2UZR
• Descriptor: RAC-alpha serine/threonine-protein kinase, INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE (3 entities in total)
• Functional Keywords: transferase, glycogen biosynthesis, translation regulation, nucleotide- binding, glycogen metabolism, atp-binding, sugar transport, nuclear protein, serine/threonine-protein kinase, transport, carbohydrate metabolism, kinase, apoptosis, phosphorylation, glucose metabolism
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 15299.85

Authors

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. (deposition date: 2007-05-01, release date: 2007-07-17, Last modification date: 2025-10-01)

Primary citation

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.
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
Nature, 448:439-444, 2007

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.

PubMed: 17611497
DOI: 10.1038/nature05933

Experimental method

X-RAY DIFFRACTION (2.46 Å)