-- Matt Sent from my iPad Begin forwarded message: From: James Fraser <jaimefraser@gmail.com<mailto:jaimefraser@gmail.com>> Date: February 20, 2014 at 6:02:33 PM PST To: "Taunton, Jack (Jack.Taunton@ucsf.edu<mailto:Jack.Taunton@ucsf.edu>)" <Jack.Taunton@ucsf.edu<mailto:Jack.Taunton@ucsf.edu>>, "Kevan Shokat" <shokat@cmp.ucsf.edu<mailto:shokat@cmp.ucsf.edu>>, Natalia Jura <natalia.jura@ucsf.edu<mailto:natalia.jura@ucsf.edu>>, "Michael Grabe" <mdgrabe@pitt.edu<mailto:mdgrabe@pitt.edu>>, David Sivak <david.sivak@gmail.com<mailto:david.sivak@gmail.com>>, "Matthew Jacobson" <matt.jacobson@ucsf.edu<mailto:matt.jacobson@ucsf.edu>>, Andrej Sali <sali@salilab.org<mailto:sali@salilab.org>>, Jim Wells <Jim.Wells@ucsf.edu<mailto:Jim.Wells@ucsf.edu>>, "Lim, Wendell" <Wendell.Lim@ucsf.edu<mailto:Wendell.Lim@ucsf.edu>>, Tanja Kortemme <kortemme@cgl.ucsf.edu<mailto:kortemme@cgl.ucsf.edu>>, "Fujimori, Danica" <Danica.Fujimori@ucsf.edu<mailto:Danica.Fujimori@ucsf.edu>>, Fletterick Robert <flett@msg.ucsf.edu<mailto:flett@msg.ucsf.edu>>, Agard Dave <agard@msg.ucsf.edu<mailto:agard@msg.ucsf.edu>>, Robert Stroud <stroud@msg.ucsf.edu<mailto:stroud@msg.ucsf.edu>>, Trever Bivona <TBivona@medicine.ucsf.edu<mailto:TBivona@medicine.ucsf.edu>>, Mark von Zastrow <vonzastrow@gmail.com<mailto:vonzastrow@gmail.com>>, "Jeff Cox" <jeffery.cox@ucsf.edu<mailto:jeffery.cox@ucsf.edu>> Subject: Cool Kinase Talk (hastily scheduled!) tomorrow (Friday) - 4PM - BH212 Matthew Young (Prof at UMichigan, was a postdoc once upon a time with John Kuriyan) was in town for BPS. He has some cool new mechanistic stories on Kinase regulation (and also some new directions on deubiquitinase inhibitors) that you all might be interested in! The seminar will be at 4PM Friday (tomorrow) in BH212. Please forward to your labs! https://dl.dropboxusercontent.com/u/7403581/matt_young.pdf If you want to meet with Matt, let me know, he'll get to campus around 2:30-3 and be free until 4. I'm happy to direct him your way - first come first served! The plan was to grab a beer after the talk at Terzetto, to which everyone is invited. Hope to see you there! And apologies for the last minute nature of the invite, Jaime ABSTRACT: Matthew Young - University of Michigan Allosteric Regulation Of Protein Kinase Enzymes Via An Electrostatic Switch That Modulates Active Site Dynamics Protein kinase (PK) enzymes are a large family of signaling proteins that play a central role in signal transduction pathways. Robust regulation of their catalytic activity is critical, and many oncogenes harbor mutations that result in misregulated PK activity. The chemical basis for how some PK regulatory factors ultimately affect the rate of chemistry is still not completely understood. We have identified a long-range electrostatic switch that we believe is used by allosteric PK regulatory factors to modulate the rate of chemistry by tuning active-site dynamics. We applied a combination of crystallography, kinetics, and molecular dynamics to determine the chemical kinetic basis for how this electrostatic switch, toggled by regulatory subunit binding, affects each step of the catalytic cycle of CDK2 kinase. We engineered point mutants to deconstruct the kinetic, dynamic, and thermodynamic consequences of the switch. We also evaluated other PKs and find that, although it has evolved to be triggered in different ways by diverse PK regulatory factors, the mechanics of this switch can be conserved. We demonstrate that a key component of the switch is that it affects a significant change in the electrostatic potential within the ATP*Mg binding site of the enzyme. This electrostatic effect is propagated through the low-dielectric protein interior and directly affects the two dominant rate-determining steps of catalysis: attenuating both the recruitment of catalytically essential Mg cofactors (affecting both kcat and KM) as well as the release of the ADP product. Conclusion: We present a chemical hypothesis that provides a mechanistic explanation for one way that a large-scale conformation transition, observed in diverse PK family members, is able to significantly affect the rate of chemistry by acting at a distance from the active site. -- -- James Fraser, PhD Assistant Professor Department of Bioengineering and Therapeutic Sciences Office: N212C Genentech Hall, Lab: N216 Genentech Hall james.fraser@ucsf.edu<mailto:james.fraser@ucsf.edu> // jaimefraser@gmail.com<mailto:jaimefraser@gmail.com> (415) 493-8421 http://www.fraserlab.com