"My long-term goal is to understand as much as possible about protein structure and function from a chemical perspective but more importantly, to apply this perspective to challenging biological problems."
I have been at Genentech since 1996. After training in chemical biology and in protein biophysics, I wanted to combine these fields. The Early Discovery Biochemistry department at Genentech is uniquely committed to investigating basic protein structure-function questions and, in particular, to understanding molecular recognition between proteins and between proteins and smaller molecules. We are especially interested in non-traditional therapeutic targets like protein-protein interactions. Projects in my lab involve diverse approaches to understanding proteins and protein complexes with the organizing theme of novel target or lead discovery in areas relevant to cancer. Our recent focus has been biochemistry of ubiquitin pathways and epigenetic regulation, in particular functional aspects of lysine acetylation.
I enjoy hosting postdocs and students in my lab. It is great to see people develop as researchers, and the enthusiasm they bring to the lab keeps our work fun. Many of the key projects in the lab come from ideas contributed by students and postdocs, and this basic research benefits our efforts to discover novel targets and drugs.
Many interesting potential targets are protein-protein interactions. However, these are not considered traditionally 'druggable' and often do not yield useful 'hits' in high-throughput screens. Past projects have therefore explored minimal requirements for protein-protein and protein-peptide recognition to better understand which targets may be tractable. For example, we discovered a general recognition motif that directs protein inhibitors of canonical Wnt signaling (SOST, DKK1) to the extracellular co-receptors LRP5 and LRP6, and we characterized the inhibitor/co-receptor complexes using mutagenesis and biophysical methods. Peptide inhibitors evolved through phage display were used to assess the potential for small-molecule intervention in this important pathway. A second major project is to understand substrate recognition and catalysis by the Polycomb E3 ubiquitin ligase BMI1/Ring1b and other related PRC1 ligases. Also in the area of ubiquitin signaling, we uncovered a phospho-regulatory mechanism for the deubiquitinase OTUD5/DUBA. Recently, we have been studying the recognition of epigenetic modifications by bromodomain “reader” modules using synthetic peptide arrays, small-molecule probes, and cellular studies. Our interest in epigenetic regulation has expanded to include chromatin remodeling complexes. A recent postdoctoral project centered on the ISWI family of chromatin remodelers: this involved proteomics, biochemistry, and cell line engineering to better understand the function of ISWI regulatory subunits.