2VO0

Structure of PKA-PKB chimera complexed with C-(4-(4-Chlorophenyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-yl)methylamine

Summary for 2VO0

• Entry DOI: 10.2210/pdb2vo0/pdb
• Related: 1CMK 1JLU 1KMU 1KMW 1Q24 1Q61 1Q62 1Q8T 1Q8U 1Q8W 1SMH 1STC 1SVE 1SVG 1SVH 1SZM 1VEB 1XH4 1XH5 1XH6 1XH7 1XH8 1XH9 1XHA 1YDR 1YDS 1YDT 2C1A 2C1B 2F7E 2GFC 2GNF 2GNG 2GNH 2GNI 2GNJ 2GNL 2JDS 2JDT 2JDV 2UVX 2UVY 2UVZ 2UW0 2UW3 2UW4 2UW5 2UW6 2UW7 2UW8 2UZT 2UZU 2UZV 2UZW 2VNW 2VO3
• Descriptor: CAMP-DEPENDENT PROTEIN KINASE, ALPHA-CATALYTIC SUBUNITPROTE, CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ALPHA, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: transferase, lipoprotein, atp-binding, phosphoprotein, serine/threonine-protein kinase, nucleotide-binding, protein kinase inhibitor, camp, kinase, nucleus, myristate, cytoplasm
• Biological source: BOS TAURUS (BOVINE); More
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 44098.45

Authors

Caldwell, J.J.,Davies, T.G.,Donald, A.,McHardy, T.,Rowlands, M.G.,Aherne, G.W.,Hunter, L.K.,Taylor, K.,Ruddle, R.,Raynaud, F.I.,Verdonk, M.,Workman, P.,Garrett, M.D.,Collins, I. (deposition date: 2008-02-08, release date: 2008-04-08, Last modification date: 2011-07-13)

Primary citation

Caldwell, J.J.,Davies, T.G.,Donald, A.,Mchardy, T.,Rowlands, M.G.,Aherne, G.W.,Hunter, L.K.,Taylor, K.,Ruddle, R.,Raynaud, F.I.,Verdonk, M.,Workman, P.,Garrett, M.D.,Collins, I.
Identification of 4-(4-Aminopiperidin-1-Yl)-7H-Pyrrolo[2,3-D]Pyrimidines as Selective Inhibitors of Protein Kinase B Through Fragment Elaboration.
J.Med.Chem., 51:2147-, 2008

PubMed Abstract: 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.

PubMed: 18345609
DOI: 10.1021/JM701437D

Experimental method

X-RAY DIFFRACTION (1.94 Å)