"We aim to find and build better therapeutics by revealing biological processes at the molecular level. My lab joins in the drug hunt by studying the structure and function of challenging membrane protein targets."
Early in my scientific career, I knew that I wanted to join the ranks of drug hunters. I was attracted to Genentech because of its solid record in translating basic research and innovative ideas to the discovery of new medicines. I feel privileged to have the opportunity to connect my past experiences studying the structure and function of membrane proteins to new discovery efforts, and in a collaborative organization focused entirely on world-class research and drug development.
Although the majority of known and potential drug targets are found in the membrane, studies of this protein class are limited, with high-resolution structures of only a small fraction of the membrane proteome reported to date. It is our aim to help facilitate the study of any therapeutic target, regardless of its cellular localization. To this end, my lab has taken on the challenge of enabling structure, function and antibody discovery studies of membrane proteins. This is always a multidisciplinary effort, giving me the opportunity to collaborate with many talented scientists across the company. We are succeeding on numerous fronts, including enabling structural studies of the Nav1.7 sodium channel, glucagon receptor, bacterial manganese transporter and many other therapeutic membrane protein targets.
Basic research on membrane proteins is confounded by many unique challenges. Opportunely, our drug discovery programs generate tools and reagents that offer distinct advantages when pursuing scientific studies of membrane targets of therapeutic interest. These include antibodies, potent small-molecule ligands, cellular assays and high-throughput techniques. I aim to enable postdocs to translate these exceptional resources into unprecedented membrane protein structures. These studies further our understanding of membrane processes at the molecular level and can also benefit future drug discovery efforts at Genentech.
Science. 2015; 350(6267)
My lab oversees the production of membrane proteins at Genentech; these may be used for structural studies, assay development or antibody discovery. Our ability to handle large numbers of these challenging targets has required significant technology development, including platforms for the rapid optimization of expression and solubilization conditions, as well as automated purification. This infrastructure has enabled structural studies in several key areas. One is focused on membrane targets for pain. We recently determined the first structure of a human voltage-gated sodium channel, that of the pain-associated Nav1.7. This structure not only revealed a new pharmacological site in Nav1.7, but also the mechanism for selective inhibition with small-molecule antagonists. We are also focused on therapeutic antibody targets in the membrane and recently determined the structure and mechanism of action of antibody inhibitors of the glucagon receptor. This work also revealed a role for the extracellular domain in negatively regulating glucagon receptor activity.
A second major interest for my lab is enabling functional and structural studies of essential bacterial membrane proteins. Many are Genentech targets for antibacterial drug development. We have recently determined the structure of an antibody inhibitor of the Staphylococcus aureus ABC importer for manganese, in complex with its protein target. This is the first example of an antibody inhibitor of a bacterial ABC transporter pathway.