Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants

Christine B Breitenlechner; Walter-Gunar Friebe; Emmanuel Brunet; Guido Werner; Klaus Graul; Ulrike Thomas; Klaus-Peter Künkele; Wolfgang Schäfer; Michael Gassel; Dirk Bossemeyer; Robert Huber; Richard A Engh; Birgit Masjost

doi:10.1021/jm049701n

Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants

J Med Chem. 2005 Jan 13;48(1):163-70. doi: 10.1021/jm049701n.

Authors

Christine B Breitenlechner¹, Walter-Gunar Friebe, Emmanuel Brunet, Guido Werner, Klaus Graul, Ulrike Thomas, Klaus-Peter Künkele, Wolfgang Schäfer, Michael Gassel, Dirk Bossemeyer, Robert Huber, Richard A Engh, Birgit Masjost

Affiliation

¹ Abteilung Strukturforschung, Max-Planck-Institut fuer Biochemie, 82152 Martinsried, Germany.

PMID: 15634010
DOI: 10.1021/jm049701n

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.

MeSH terms

Adenosine Triphosphate / metabolism
Binding Sites
Crystallography, X-Ray
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases / chemistry*
Cyclic AMP-Dependent Protein Kinases / genetics
Cyclic AMP-Dependent Protein Kinases / metabolism*
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism*
Models, Molecular
Mutation
Protein Conformation
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / chemistry
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Reproducibility of Results
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Proto-Oncogene Proteins
Adenosine Triphosphate
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Cyclic AMP-Dependent Protein Kinases

Associated data

PDB/1XH4-9
PDB/1XHA