1xh4

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spinqualitylabelsall models 1xh4, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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 R69 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

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