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Separated at Birth, the Evolution of Kinase Dynamics Over a Few Billion Years
Author(s) -
Kern Dorothee
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.240.3
Subject(s) - kinase , abl , drug discovery , computational biology , mechanism (biology) , tyrosine kinase , chemistry , biology , biochemistry , signal transduction , philosophy , epistemology
I will present our recent exploration of the evolution of the fascinating rate acceleration of enzymes and the evolutionary origin of allostery. The secret of enzymes lies in their ability to partition energetic contributions among many atoms in a well‐coordinated style. To unravel these secrets, the evolution of protein dynamics in the family of protein kinases is spied on to provide a comprehensive description of enzyme catalysis in the form of an energy landscape. Ancestor resurrection combined with modern biophysical characterization combining NMR, fast kinetics and x‐ray crystallography shed light into evolution of protein function to create more sophisticated biomolecules. The evolution of energy landscapes offer a larger variety of signaling mechanisms and sophisticated enzyme catalysis compared to evolution of structure alone. Interestingly, our time‐travel delivered an additional unusual twist, the discovery of the molecular origin of the modern cancer drug Gleevec for the human tyrosine kinase Abl: Protein kinases are attractive drug targets against cancer due to their central role in cellular regulation, but the similarity of their active site has hampered the development of specific drugs. One of the major success stories has been Gleevec, a highly selective inhibitor of Abl kinase. The molecular mechanism underlying Gleevec's selectivity for Abl has not been solved since the discovery of the drug 20 years ago despite large efforts. Gleevec's selectivity is puzzling because the drug‐binding pocket with Gleevec bound is nearly identical between Abl and Src and other homologous kinases that have very weak affinity for the drug. I will present how the characterization of the evolution of kinase dynamics over 1 billion years reveals the mechanism responsible Gleevec's selectivity. The results simultaneously shed light on the longstanding paradox of the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve for catalysis. The resurrection of the tyrosine kinase ancestors explores a key event in the history of life, the development of multicellularity coinciding with the explosion of the kinome. Interestingly, gleevec takes advantage of evolutionary differences among the kinases “by accident” thereby leading to one of the most potent and specific cancer drugs to date.