Alison Donnelly Axtman

Mentors: Lynette Cegelski and Paul Wender

Project Title: Interrogating PKC Complex with NMR

Biography

Alison Donnelly Axtman is a synthetic medicinal chemist with a keen interest in projects that bridge the chemical biology interface. Since leaving her hometown of Buffalo, Alison has been moving westward across the United States. Alison earned dual degrees in Chemistry and Spanish from Case Western Reserve University before choosing the University of Kansas for her graduate studies in Medicinal Chemistry. Alison joined the Wender lab in April 2011 and works on several projects aimed at selectively modulating proteins implicated in disease-propagating pathways to develop first-in-class small molecule therapeutics. 

Research Summary

PKC isozymes are implicated in a wide variety of diseases including cancer, cardiovascular disease, diabetes, stroke, Alzheimer’s disease, neuropathic pain, and HIV/AIDS. The ability to specifically target PKC has huge potential in their treatment. Isozyme-specific PKC agonists/inhibitors are needed to enable the targeting of individual disease states. Thus far, the approach introduced by the Wender group based on computer analyses and design of PKC activators has proven effective in the design of potent, radically-simplified PKC ligands, but does not provide an understanding of the structure and dynamics of the ligand/PKC complex in a membrane-associated system. In order to better target individual PKC isoforms, biologically relevant structural determination of PKC isoforms is critical. Unfortunately, such structural analyses have been hampered by the requirement of a phospholipid environment to allow for proper folding of PKC prior to binding PKC activators. With the Cegelski lab, Rotational-Echo Double-Resonance (REDOR) NMR is a solid-state NMR technique that would provide invaluable structural information in this circumstance. Significantly, by relying upon strategically and selectively incorporated isotope labels, REDOR NMR can provide invaluable structural information in phospholipid-associated PKC complexes. REDOR provides a direct measure of short- and long-range heteronuclear dipolar couplings between pairs of rare spins. The couplings contain information on both internuclear distances and orientations. REDOR NMR would provide critical structural information related to the protein-ligand and protein-lipid interactions. Thus, the bioactive bound conformations of PKC ligands, the proximity of ligands and PKC residues to lipid headgroups, and interactions between PKC and ligands can be determined.