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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, Künkele KP, Schäfer W, Gassel M, Bossemeyer D, Huber R, Engh RA, Masjost B
J Med Chem 48 163-70 (2005)
Related entries: 1sve, 1svg, 1svh, 1veb, 1xh4, 1xh5, 1xh6, 1xh7, 1xh8, 1xh9

Cited: 25 times
EuropePMC logo PMID: 15634010

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.

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  3. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. Sunami T, Byrne N, Diehl RE, Funabashi K, Hall DL, Ikuta M, Patel SB, Shipman JM, Smith RF, Takahashi I, Zugay-Murphy J, Iwasawa Y, Lumb KJ, Munshi SK, Sharma S. J Biol Chem 285 4587-4594 (2010)
  4. Adenylyl cyclase type VI increases Akt activity and phospholamban phosphorylation in cardiac myocytes. Gao MH, Tang T, Guo T, Miyanohara A, Yajima T, Pestonjamasp K, Feramisco JR, Hammond HK. J Biol Chem 283 33527-33535 (2008)
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  14. Geometric Deep Learning for Structure-Based Ligand Design. Powers AS, Yu HH, Suriana P, Koodli RV, Lu T, Paggi JM, Dror RO. ACS Cent Sci 9 2257-2267 (2023)
  15. How Far Are We from the Rapid Prediction of Drug Resistance Arising Due to Kinase Mutations? Erguven M, Karakulak T, Diril MK, Karaca E. ACS Omega 6 1254-1265 (2021)
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  17. Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy. Qin J, Zhang J, Lin L, Haji-Ghassemi O, Lin Z, Woycechowsky KJ, Van Petegem F, Zhang Y, Yuchi Z. Elife 11 e75346 (2022)


Related citations provided by authors (1)

  1. Structure-based optimization of novel azepane derivatives as PKB inhibitors.. Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, Masjost B J Med Chem 47 1375-90 (2004)

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