1XH6

Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants

Summary for 1XH6

• Entry DOI: 10.2210/pdb1xh6/pdb
• Related: 1SVE 1SVG 1SVH 1VEB 1XH4 1XH5 1XH7 1XH8 1XH9 1XHA
• Descriptor: cAMP-dependent protein kinase, alpha-catalytic subunit, cAMP-dependent protein kinase inhibitor, alpha form, N-(4-{[4-(2-HYDROXY-5-PIPERIDIN-1-YLBENZOYL)BENZOYL]AMINO}AZEPAN-3-YL)ISONICOTINAMIDE, ... (4 entities in total)
• Functional Keywords: pka, kinase-inhibitor-complex, serine/threonine-protein kinase, balanol derivative, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Bos taurus (cattle); More
• Cellular location: Cytoplasm: P00517
• Total number of polymer chains: 2
• Total formula weight: 43474.47

Authors

Breitenlechner, C.B.,Friebe, W.-G.,Brunet, E.,Werner, G.,Graul, K.,Thomas, U.,Kuenkele, K.-P.,Schaefer, W.,Gassel, M.,Bossemeyer, D.,Huber, R.,Engh, R.A.,Masjost, B. (deposition date: 2004-09-17, release date: 2005-09-17, Last modification date: 2024-10-30)

Primary citation

Breitenlechner, C.B.,Friebe, W.-G.,Brunet, E.,Werner, G.,Graul, K.,Thomas, U.,Kuenkele, K.-P.,Schaefer, W.,Gassel, M.,Bossemeyer, D.,Huber, R.,Engh, R.A.,Masjost, B.
Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants
J.Med.Chem., 48:163-170, 2005

PubMed Abstract: 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.

PubMed: 15634010
DOI: 10.1021/jm049701n

Experimental method

X-RAY DIFFRACTION (1.9 Å)