Natalie Ahn (University of Coloardo, Boulder)

Natalie Ahn (University of Coloardo, Boulder)

Butler Seminar Series

Event Date/Location

December 7, 2016 - 12:00 pm
Thomas Laboratory 003

Speaker

  • Photo of Natalie Ahn

    Natalie Ahn

    Professor of Distinction
    University of Colorado-Boulder

    Natalie Ahn received her PhD with Judith Klinman at U California, Berkeley where she studied the enzymology of dopamine monooxygenase.  She carried out postdoctoral work with Edwin Krebs at U. Washington, Seattle where she was an early discoverer of MAP kinases and the first to describe MAP kinase kinases.  Research goals are to discover new mechanisms underlying the regulation and function of signaling pathways.  An important theme has been to investigate cell responses to MAP kinases and other pathways, by developing and applying new methods in proteomics and mass spectrometry.  Dr. Ahn serves as the current President of the American Society of Biochemistry and Molecular Biology

Topic

Phosphorylation-regulated protein dynamics in kinase regulation and implications for inhibitor design: The case of ERK2

The MAP kinases, extracellular-regulated protein kinases 1 & 2 (ERK1/2), are important drug targets for cancers caused by oncogenic mutations in RAS and B-RAF. Preclinical studies show that cells from metastatic cancers with acquired resistance to RAF and MKK inhibitors can be effectively killed using small molecule inhibitors of ERK, some of which are in early stage clinical trials. An important unsolved question is: How is ERK2 activated by dual phosphorylation at Thr and Tyr residues, both catalyzed by MKK1/2?  Using hydrogen exchange mass spectrometry and NMR relaxation dispersion experiments, we discovered that the activation of ERK2 involves the release of protein motions, leading to global exchange between conformational states which we believe function to enable productive nucleotide binding. An intriguing possibility is that these phosphorylation-regulated dynamics may be coupled to steps in catalytic turnover.  Importantly, high affinity ERK inhibitors, which are effective towards cells with acquired resistance, show properties of conformation selection in a manner correlating with slow dissociation. Our findings suggest that the regulated dynamics of ERK2 are exploited by these inhibitors to improve their kinetic properties and efficacy.

Audience

Free and open to the university community and the public.

Host

Ileana Cristea, Department of Molecular Biology