Scientist Profile

I have been at Genentech since 1996. After training in bio-organic chemistry and in protein biophysics, I wanted to combine these fields. The Protein Engineering 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. 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.

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. Work in this area led us to study individual residue contributions to strand-strand recognition in β-sheet proteins. These studies initially involved structural stability assays in peptides, leading to the design of a family of very small and stably folded β-hairpins (tryptophan zippers). To extend our work to larger proteins, we developed a quantitative phage display method to probe cross-strand residue pairing in β-sheets.

More recently, the lab has been focused on the biochemistry and cellular function of mitotic protein kinases. We have probed activation mechanisms and cellular function by site-directed mutagenesis and applied phage display and truncation mutagenesis to define structurally important regions of reported binding partners. These subdomains are excellent starting points for structural studies by NMR or x-ray crystallography. Finally, we have employed proteomic techniques (affinity purification/mass spectrometry and yeast two-hybrid methods) to discover new binding partners and fit them into pathways. We are now starting new projects in the areas of epigenetic modifications and deubiquitinases.

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My Focus

I collaborate extensively with structural biologists in Protein Engineering, medicinal chemists, and with colleagues in the Oncology and Cell Cycle areas.

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. 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.

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Publications & Recognition

• The mitotic regulator Survivin binds as a monomer to its functional interactor Borealin.
• J Biol Chem 2007 Nov 30; 282(48): 35018-23.
• Bourhis E, Hymowitz SG, Cochran AG.
• View Abstract on PubMed

• BAFF/BLyS receptor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-kappaB2.
• Immunity 2002 Oct; 17(4): 515-24.
• Kayagaki N, Yan M, Seshasayee D, Wang H, Lee W, French DM, Grewal IS, Cochran AG, Gordon NC, Yin J, Starovasnik MA, Dixit VM.
• View Abstract on PubMed

• Quantifying beta-sheet stability by phage display.
• J Mol Biol 2002 Sep 6; 322(1): 179-88
• Distefano MD, Zhong A, Cochran AG.
• View Abstract on PubMed