4EKK: Akt1 with AMP-PNP

Citation:
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.
PDB ID: 4EKKDownload
MMDB ID: 99947
PDB Deposition Date: 2012/4/9
Updated in MMDB: 2012/05
Experimental Method:
x-ray diffraction
Resolution: 2.8  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4EKK: dimeric; determined by author and by software (PISA)
Molecular Components in 4EKK
Label Count Molecule
Proteins (2 molecules)
1
Rac-alpha Serine/threonine-protein Kinase(Gene symbol: AKT1)
Molecule annotation
1
Glycogen Synthase Kinase-3 Beta(Gene symbol: GSK3B)
Molecule annotation
Chemicals (3 molecules)
1
1
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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