4EKK
Akt1 with AMP-PNP
Summary for 4EKK
| Entry DOI | 10.2210/pdb4ekk/pdb |
| Related | 4EKL |
| Descriptor | RAC-alpha serine/threonine-protein kinase, Glycogen synthase kinase-3 beta, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total) |
| Functional Keywords | phosphotransferase, transferase |
| Biological source | Homo sapiens (human) More |
| Cellular location | Cytoplasm: P31749 P49841 |
| Total number of polymer chains | 4 |
| Total formula weight | 82412.52 |
| Authors | Wu, W.-I.,Vigers, G.P.A.,Morales, T.H.,Brandhuber, B.J. (deposition date: 2012-04-09, release date: 2012-05-23, Last modification date: 2024-10-09) |
| Primary citation | Lin, K.,Lin, J.,Wu, W.I.,Ballard, J.,Lee, B.B.,Gloor, S.L.,Vigers, G.P.,Morales, T.H.,Friedman, L.S.,Skelton, N.,Brandhuber, B.J. An ATP-Site On-Off Switch That Restricts Phosphatase Accessibility of Akt. Sci.Signal., 5:ra37-ra37, 2012 Cited by PubMed Abstract: The protein serine-threonine kinase Akt undergoes a substantial conformational change upon activation, which is induced by the phosphorylation of two critical regulatory residues, threonine 308 and serine 473. Paradoxically, treating cells with adenosine 5'-triphosphate (ATP)-competitive inhibitors of Akt results in increased phosphorylation of both residues. We show that binding of ATP-competitive inhibitors stabilized a conformation in which both phosphorylated sites were inaccessible to phosphatases. ATP binding also produced this protection of the phosphorylated sites, whereas interaction with its hydrolysis product adenosine 5'-diphosphate (ADP) or allosteric Akt inhibitors resulted in increased accessibility of these phosphorylated residues. ATP-competitive inhibitors mimicked ATP by targeting active Akt. Forms of Akt activated by an oncogenic mutation or myristoylation were more potently inhibited by the ATP-competitive inhibitors than was wild-type Akt. These data support a new model of kinase regulation, wherein nucleotides modulate an on-off switch in Akt through conformational changes, which is disrupted by ATP-competitive inhibitors. PubMed: 22569334DOI: 10.1126/scisignal.2002618 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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