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Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Expanding the conformational space of structure/function relationship of tyrosine kinases

Src and Syk tyrosine kinases work together in immune signaling and are targets of considerable interest for therapeutics. Molecular dynamics simulations combined with NMR spectroscopy are used to gain insights into the molecular basis of their function. The transition pathway for conformational activation of Src kinases has features that appear to be common across the kinome, and provide a rationale for a diverse set of regulatory complexes for which the basis of regulation is unclear from structure alone. Second, recent NMR studies find that substrate recognition differs within the one and only group of tyrosine kinases in the kinome (TK group). This finding thus alters the existing paradigm whereby substrate recognition differs between the Tyr kinases and the Ser/Thr kinases. Now, the distinction falls within the TK group of the kinome. Third, a unique allosteric mechanism for controlling the interaction of Syk with membrane receptors has been investigated using NMR and calorimetry to dissect physical features of the effect of phosphorylation at a distal tyrosine residue that result in altered binding affinity. Interestingly, we find the mechanism defies entropy/enthalpy compensation. This talk will cover some part of these three stories.

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Bradley Dickson
Chao Feng
He Huang
Mehul Joshi
Carol Beth Post

Departments of Medicinal Chemistry and Biological Sciences
Purdue University
West Lafayette, IN 47906
cbp@purdue.edu