2VO6: Structure Of Pka-Pkb Chimera Complexed With 4-(4- Chlorobenzyl)-1-(7h-Pyrrolo(2,3-D)pyrimidin-4-Yl)piperidin- 4-Ylamine

Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.
PDB ID: 2VO6Download
MMDB ID: 63647
PDB Deposition Date: 2008/2/8
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 1.97  Å
Source Organism:
Bos taurus
Similar Structures:
Biological Unit for 2VO6: dimeric; determined by software (PQS)
Molecular Components in 2VO6
Label Count Molecule
Proteins (2 molecules)
Camp-dependent Protein Kinase, Alpha-catalytic Subunit(Gene symbol: PRKACA)
Molecule annotation
Camp-dependent Protein Kinase Inhibitor Alpha(Gene symbol: PKIA)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB