Abstract:

Membrane proteins are involved in numerous vital biological processes, including transport, signal transduction and the enzymes in a variety of metabolic pathways. Integral membrane proteins account for up to 30% of the human proteome and make up more than half of all currently marketed therapeutic targets. Unfortunately, membrane proteins are inherently recalcitrant to study using the normal toolkit available to scientists, and one is most often left with the challenge of finding inhibitors, activators and specific antibodies using a denatured or detergent solubilized aggregate.  Often, since membrane proteins are inherently insoluble and prone to aggregation and oligomerization. in solution, the active state of interest is obscured.  The Nanodisc platform circumvents these challenges by providing a self-assembled system that renders typically insoluble, yet biologically and pharmacologically significant, targets such as receptors, transporters, enzymes, and viral antigens soluble in aqueous media.  Because Nanodisc constructs provide a native-like bilayer environment that maintain a target’s functional activity, they are a versatile tool in the study of membrane proteins such as ion channels, GPCRs, cytochrome P450s, blood coagulation factors, various toxins and viral entities as well as a plethora of pharmaceutical targets.  In addition to the opportunities in drug discovery, Nanodiscs provide a nanometer scale vehicle for the in vivo delivery of amphipathic drugs, therapeutic lipids, tethered nucleic acids, imaging agents and active protein complexes.  In my presentation I will summarize the use of Nanodiscs for structural biology, sensing and imaging as well as recent work seeking mechanistic understanding of oncogenic cancer signaling by KRas4b.