Nanobodies and protein engineering

Antibody fragments are critical tools in every area of modern biological research. In collaboration with the Manglik Lab (UCSF) we have developed a new platform for rapid and low-cost discovery of single-domain camelid antibody fragments ("nanobodies"). Using this approach, we can now routinely discover and optimize conformationally selective nanobodies targeting membrane proteins, enabling structural and functional studies that would be impossible without these tools. With an average turnaround time of three to four weeks, nanobody discovery in vitro is far faster and cheaper than animal immunization. Our synthetic nanobody library is available for non-profit research from Kerafast: For-profit organizations can license the library from the Harvard Office for Technology Development.

G protein-coupled receptors

G protein-coupled receptors (GPCRs) are cell-surface receptors that regulate neurotransmission, cardiovascular function, metabolic homeostasis, and many other processes. Due to their central role in human physiology, these receptors are among the most important targets of therapeutic drugs. To better understand GPCR signal transduction at a molecular level, we are using structural biology techniques including lipidic cubic phase (LCP) crystallography and cryo-electron microscopy to characterize GPCR structure and conformational change. In addition, we are using antibody engineering approaches to develop GPCR-modulating antibody fragments to investigate receptor biology and therapeutic potential.

Other signaling pathways

In addition to work on GPCRs, we are also interested in membrane proteins that remain less extensively studied. These include the sigma-1 and sigma-2 receptors, the CD81-CD19 B cell co-receptor complex, and membrane-bound enzymes and transporters that assemble and maintain the bacterial cell envelope.