1xh4
From Proteopedia
(New page: 200px<br /> <applet load="1xh4" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xh4, resolution 2.45Å" /> '''Crystal Structures ...) |
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| - | [[Image:1xh4.gif|left|200px]]<br /> | + | [[Image:1xh4.gif|left|200px]]<br /><applet load="1xh4" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xh4" size=" | + | |
caption="1xh4, resolution 2.45Å" /> | caption="1xh4, resolution 2.45Å" /> | ||
'''Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants'''<br /> | '''Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a | + | Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design. |
==About this Structure== | ==About this Structure== | ||
| - | 1XH4 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with R69 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http:// | + | 1XH4 is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=R69:'>R69</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XH4 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Bossemeyer, D.]] | [[Category: Bossemeyer, D.]] | ||
| - | [[Category: Breitenlechner, C | + | [[Category: Breitenlechner, C B.]] |
[[Category: Brunet, E.]] | [[Category: Brunet, E.]] | ||
| - | [[Category: Engh, R | + | [[Category: Engh, R A.]] |
| - | [[Category: Friebe, W | + | [[Category: Friebe, W G.]] |
[[Category: Gassel, M.]] | [[Category: Gassel, M.]] | ||
[[Category: Graul, K.]] | [[Category: Graul, K.]] | ||
[[Category: Huber, R.]] | [[Category: Huber, R.]] | ||
| - | [[Category: Kuenkele, K | + | [[Category: Kuenkele, K P.]] |
[[Category: Masjost, B.]] | [[Category: Masjost, B.]] | ||
[[Category: Schaefer, W.]] | [[Category: Schaefer, W.]] | ||
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[[Category: serine/threonine-protein kinase]] | [[Category: serine/threonine-protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:54:43 2008'' |
Revision as of 13:54, 21 February 2008
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Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants
Overview
Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.
About this Structure
1XH4 is a Protein complex structure of sequences from Bos taurus with as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants., Breitenlechner CB, Friebe WG, Brunet E, Werner G, Graul K, Thomas U, Kunkele KP, Schafer W, Gassel M, Bossemeyer D, Huber R, Engh RA, Masjost B, J Med Chem. 2005 Jan 13;48(1):163-70. PMID:15634010
Page seeded by OCA on Thu Feb 21 15:54:43 2008
Categories: Bos taurus | Non-specific serine/threonine protein kinase | Protein complex | Bossemeyer, D. | Breitenlechner, C B. | Brunet, E. | Engh, R A. | Friebe, W G. | Gassel, M. | Graul, K. | Huber, R. | Kuenkele, K P. | Masjost, B. | Schaefer, W. | Thomas, U. | Werner, G. | R69 | Balanol derivative | Kinase-inhibitor-complex | Pka | Serine/threonine-protein kinase
