Personal tools
You are here: Home Administration Chemistry & Biochemistry Department Events 2018 January Biochemistry Seminar: Markus Seeliger, "Kinase dynamics underlying the specificity of inhibitors and promiscuity of kinases"

Biochemistry Seminar: Markus Seeliger, "Kinase dynamics underlying the specificity of inhibitors and promiscuity of kinases"

Markus Seeliger, Assoc Professor, Dept of Pharmacological Sciences, SUNY Stony Brook University School of Medicine, "Kinase dynamics underlying the specificity of inhibitors and promiscuity of kinases"
When Jan 31, 2018
from 12:00 PM to 01:00 PM
Where CUNY ASRC Main Auditorium
Contact Name
Contact Phone 212-650-8803
Add event to calendar vCal
iCal

ABSTRACT

The catalytic domain of protein tyrosine kinases can interconvert between active and inactive conformations in response to regulatory inputs. We have surveyed by NMR the effect of conformationally-selective inhibitors on kinase backbone dynamics. We find that inhibitor binding and activation loop autophosphorylation induces dynamic changes across the entire kinase. We identify a highly conserved amino acid, Gly449, that is necessary for Src activation. Finally, we show for the first time how the SH3-SH2 domains perturb the dynamics of the kinase domain in the context of the full length protein. We provide experimental support for long-range communication in Src kinase that leads to the relative stabilization of active or inactive conformations and modulation of substrate affinity.

ATP-competitive kinase inhibitors often bind several kinases due to the high conservation of the ATP binding pocket. Through hierarchical clustering analysis of kinome profiling data of a large inhibitor set (PKIS2) we found a set of unusually promiscuous kinases, that appear to prefer the DFG-Aps-out inactive conformation. We crystallized one of these kinases, DDR1 with known type 1 inhibitors and surpisingly, we find that DDR1 binds these inhibitors in the DFG-Asp out conformation, typically observed for type-2 inhibitors. Using computational simulations and mutational analysis, we determined that DDR1 has an unusually stable DFG-Asp-Out conformation. We propose that the promiscuous behavior of DDR1 and other promiscuous tyrosine kinases is related to its stable inactive conformation, which forms a binding pocket capable of binding a diverse range of chemically diverse inhibitors.

More information about this event…