John Karanicolas photoJohn Karanicolas
Assistant Professor, Molecular Biosciences
University of Kansas

Modulating protein function by rational design

Mentor: Mario Rivera , Professor, Chemistry
The University of Kansas

Dr. Karanicolas's goal for his research is to provide insight into the utility of a novel approach for designing pharmacological control into enzymes. Karanicolas thinks such an approach would find immediate and widespread use for identifying in vivo substrates of enzymes involved in post-translational modification pathways.

In recent years chemical biology has been used to engineer small-molecule dependent function into a variety of biomolecules. The report of a general approach to modulating protein-protein interactions using rapamycin led to the immediate and widespread adoption of this technology, but this approach is not adaptable to control enzyme function in an analogous way.

The Karanicolas research group has recently conceived and implemented a novel approach for designing pharmacological control into enzymes. Karanicolas's central hypothesis is that the mechanism he observed in a first model enzyme will prove general enough to allow small-molecule modulation of other enzymes in living cells. Such a technique should be amenable to activation by bio-orthogonal ligands and should not alter the substrate specificity of the resulting enzyme. The objective of this application is to evaluate the suitability of his approach for small molecule modulation of enzyme function, in light of these two criteria.

He proposes to meet his objective by pursuit of the following two specific aims:

  1. Design ligand-dependent luciferase activity.
  2. Test substrate selectivity upon rescue of histone lysine methyltransferase activity.