Our core science is organic chemistry, and the projects reflect this focus. Microtubules are polymers composed of the protein called tubulin, and nature has provided us with a variety of natural products that bind to tubulin and interfere with cytoskeletal function. Phomopsin A is the most potent microtubule-depolymerizing agent yet identified. We are pursuing the synthesis of phomopsin as well as several variants of the natural product designed to probe the requirements for tubulin binding and microtubule depolymerization. These compounds exhibit cellular effects that we use to study components of the cytoskeleton and its associated signaling pathways.
Many organic molecules bind to their protein receptors with only moderate affinity.
We have devised a method to improve these binding events by borrowing additional surface area from abundant cellular proteins. We use synthetic chemistry to prepare bifunctional molecules that are capable of binding to two different proteins simultaneously. The resulting trimeric complex may possess additional protein-protein interactions that contribute favorably to the stability of the complex. T.J. Wandless, J. Am. T.J. Wandless, and G.R. Crabtree, Proc.