2uzr: Difference between revisions
New page: left|200px<br /> <applet load="2uzr" size="450" color="white" frame="true" align="right" spinBox="true" caption="2uzr, resolution 1.94Å" /> '''A TRANSFORMING MUTA... |
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[[Image:2uzr. | [[Image:2uzr.jpg|left|200px]]<br /><applet load="2uzr" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2uzr, resolution 1.94Å" /> | caption="2uzr, resolution 1.94Å" /> | ||
'''A TRANSFORMING MUTATION IN THE PLECKSTRIN HOMOLOGY DOMAIN OF AKT1 IN CANCER (AKT1-PH_E17K)'''<br /> | '''A TRANSFORMING MUTATION IN THE PLECKSTRIN HOMOLOGY DOMAIN OF AKT1 IN CANCER (AKT1-PH_E17K)'''<br /> | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
2UZR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http:// | 2UZR is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2UZR OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: transport]] | [[Category: transport]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:33:25 2008'' | ||
Revision as of 15:33, 23 January 2008
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A TRANSFORMING MUTATION IN THE PLECKSTRIN HOMOLOGY DOMAIN OF AKT1 IN CANCER (AKT1-PH_E17K)
OverviewOverview
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.
About this StructureAbout this Structure
2UZR is a Single protein structure of sequence from Homo sapiens. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer., Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE, Nature. 2007 Jul 26;448(7152):439-44. Epub 2007 Jul 4. PMID:17611497
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- Homo sapiens
- Non-specific serine/threonine protein kinase
- Single protein
- Bittner, M.
- Blanchard, K.L.
- Boguslawski, S.
- Briggs, S.L.
- Carpten, J.D.
- Donoho, G.P.
- Du, J.
- Faber, A.L.
- Horn, C.
- Hostetter, G.
- Lai, M.H.
- Lin, A.
- Moses, T.Y.
- Mousses, S.
- Patel, K.
- Qian, Y.W.
- Robbins, C.M.
- Savage, S.
- Schevitz, R.
- Thomas, J.E.
- Touchman, J.
- Tucker-Kellogg, G.
- Uhlik, M.
- Zeckner, D.J.
- Apoptosis
- Atp-binding
- Carbohydrate metabolism
- Glucose metabolism
- Glycogen biosynthesis
- Glycogen metabolism
- Kinase
- Nuclear protein
- Nucleotide-binding
- Phosphorylation
- Serine/threonine-protein kinase
- Sugar transport
- Transferase
- Translation regulation
- Transport