4EKL

Akt1 with GDC0068

Summary for 4EKL

• Entry DOI: 10.2210/pdb4ekl/pdb
• Related: 4EKK
• Descriptor: RAC-alpha serine/threonine-protein kinase, (2S)-2-(4-chlorophenyl)-1-{4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperazin-1-yl}-3-(propan-2-ylamino)propan-1-one (3 entities in total)
• Functional Keywords: phosphotransferase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P31749
• Total number of polymer chains: 1
• Total formula weight: 39924.96

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: 2024-11-20)

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

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: 22569334
DOI: 10.1126/scisignal.2002618

Experimental method

X-RAY DIFFRACTION (2 Å)