2ojf
From Proteopedia
(New page: 200px<br /><applet load="2ojf" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ojf, resolution 2.10Å" /> '''Crystal structure of...) |
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| - | [[Image:2ojf.gif|left|200px]]<br /><applet load="2ojf" size=" | + | [[Image:2ojf.gif|left|200px]]<br /><applet load="2ojf" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2ojf, resolution 2.10Å" /> | caption="2ojf, resolution 2.10Å" /> | ||
'''Crystal structure of Protein Kinase A in complex with Pyridine-Pyrazolopyridine based inhibitors'''<br /> | '''Crystal structure of Protein Kinase A in complex with Pyridine-Pyrazolopyridine based inhibitors'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Thr-211 is one of three different amino acid residues in the kinase domain | + | Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed. |
==About this Structure== | ==About this Structure== | ||
| - | 2OJF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with 4PY as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] Full crystallographic information is available from [http:// | + | 2OJF is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=4PY:'>4PY</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OJF OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: cAMP-dependent protein kinase]] | [[Category: cAMP-dependent protein kinase]] | ||
| - | [[Category: Stoll, V | + | [[Category: Stoll, V S.]] |
[[Category: 4PY]] | [[Category: 4PY]] | ||
[[Category: akt]] | [[Category: akt]] | ||
[[Category: protein kinase a]] | [[Category: protein kinase a]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:19:07 2008'' |
Revision as of 16:19, 21 February 2008
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Crystal structure of Protein Kinase A in complex with Pyridine-Pyrazolopyridine based inhibitors
Overview
Thr-211 is one of three different amino acid residues in the kinase domain of protein kinase B/Akt as compared to protein kinase A (PKA), a closely related analog in the same AGC family. In an attempt to improve the potency and selectivity of our indazole-pyridine series of Akt inhibitors over PKA, efforts have focused on the incorporation of a chemical functionality to interact with the hydroxy group of Thr-211. Several substituents including an oxygen anion, amino, and nitro groups have been introduced at the C-6 position of the indazole scaffold, leading to a significant drop in Akt potency. Incorporation of a nitrogen atom into the phenyl ring at the same position (i.e., 9f) maintained the Akt activity and, in some cases, improved the selectivity over PKA. The structure-activity relationships of the new pyridine-pyrazolopyridine series of Akt inhibitors and their structural features when bound to PKA are also discussed.
About this Structure
2OJF is a Single protein structure of sequence from Bos taurus with as ligand. Active as cAMP-dependent protein kinase, with EC number 2.7.11.11 Full crystallographic information is available from OCA.
Reference
Design and synthesis of pyridine-pyrazolopyridine-based inhibitors of protein kinase B/Akt., Zhu GD, Gong J, Gandhi VB, Woods K, Luo Y, Liu X, Guan R, Klinghofer V, Johnson EF, Stoll VS, Mamo M, Li Q, Rosenberg SH, Giranda VL, Bioorg Med Chem. 2007 Mar 15;15(6):2441-52. Epub 2007 Jan 17. PMID:17258463
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