2uzr: Difference between revisions
From Proteopedia
Jump to navigationJump to search
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... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2uzr. | [[Image:2uzr.jpg|left|200px]]<br /><applet load="2uzr" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2uzr" size=" | |||
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 /> | ||
| Line 6: | Line 5: | ||
==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== | ||
| Line 58: | Line 54: | ||
[[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'' | ||
