2vo7
From Proteopedia
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'''STRUCTURE OF PKA COMPLEXED WITH 4-(4-CHLOROBENZYL)-1-(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)PIPERIDIN-4-YLAMINE''' | '''STRUCTURE OF PKA COMPLEXED WITH 4-(4-CHLOROBENZYL)-1-(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)PIPERIDIN-4-YLAMINE''' | ||
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| + | ==Overview== | ||
| + | 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. | ||
==About this Structure== | ==About this Structure== | ||
2VO7 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO7 OCA]. | 2VO7 is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO7 OCA]. | ||
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| + | ==Reference== | ||
| + | Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration., Caldwell JJ, Davies TG, Donald A, McHardy T, Rowlands MG, Aherne GW, Hunter LK, Taylor K, Ruddle R, Raynaud FI, Verdonk M, Workman P, Garrett MD, Collins I, J Med Chem. 2008 Apr 10;51(7):2147-57. Epub 2008 Mar 18. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18345609 18345609] | ||
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
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[[Category: Serine/threonine-protein kinase]] | [[Category: Serine/threonine-protein kinase]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 30 13:35:01 2008'' | ||
Revision as of 10:35, 30 April 2008
STRUCTURE OF PKA COMPLEXED WITH 4-(4-CHLOROBENZYL)-1-(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)PIPERIDIN-4-YLAMINE
Overview
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.
About this Structure
2VO7 is a Protein complex structure of sequences from Bos taurus. Full crystallographic information is available from OCA.
Reference
Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration., Caldwell JJ, Davies TG, Donald A, McHardy T, Rowlands MG, Aherne GW, Hunter LK, Taylor K, Ruddle R, Raynaud FI, Verdonk M, Workman P, Garrett MD, Collins I, J Med Chem. 2008 Apr 10;51(7):2147-57. Epub 2008 Mar 18. PMID:18345609 Page seeded by OCA on Wed Apr 30 13:35:01 2008
Categories: Bos taurus | Protein complex | CAMP-dependent protein kinase | Aherne, G W. | Caldwell, J J. | Collins, I. | Davies, T G. | Donald, A. | Garrett, M D. | Hunter, L K. | Mchardy, T. | Raynaud, F I. | Rowlands, M G. | Ruddle, R. | Taylor, K. | Verdonk, M. | Workman, P. | Atp-binding | Camp | Cytoplasm | Kinase | Lipoprotein | Myristate | Nucleotide-binding | Nucleus | Phosphoprotein | Protein kinase inhibitor | Serine/threonine-protein kinase | Transferase
