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Fernando Bazan Senior Scientist: Protein Engineering |
"Lab charter
To investigate conserved mechanisms of signaling at the core of important immune and developmental pathways, their variation in human diseases like autoimmunity and cancer, and the use of structure-based experimental approaches to discern the best points and means of therapeutic intervention. We aim to both lead and catalyze cutting-edge cross-disciplinary research and drug discovery work, utilizing strong biochemical, structural and computational tools. Several projects spanning a broad set of fields at Genentech are summarized below.
Cytokine signaling pathways (immunology, cancer)
Protein fold and interaction prediction for cytokines and their cognate receptors (using sensitive fold recognition, docking and modeling tools) in order to decipher molecular rules of engagement and specificity, with the aim of carrying out appropriate biochemical, cell-based and structural (X-ray or NMR) experiments to test the validity or accuracy of the prediction. We work with members of the far-flung family of hemopoietic (helical) cytokines and receptors, and also with the beta-trefoil class of factors (interleukin-1 and FGF homologs), cystine-knot growth factors (like neurotrophins and IL-17s), beta-jellyrolls (TNFs and C1qs) and others. Innate immune pathways (triggered for instance by TLRs in response to pathogens) are also under study. In equal measure to studying receptor-ligand interactions, we are interested in signaling events occurring in transient complexes assembled around the respective receptor intracellular domains, for instance the specific binding of JAKs and STATs to hemopoietic receptor cytoplasmic regions. These interactions are just as precise and regulated as the extracellular engagements, and we are hunting for therapeutic points of intervention with isolated domains, phage-display peptides, peptidomimetics and small-molecule compounds.
Enzyme allosteric inhibition (cancer pathways)
Focusing mostly on kinases, we seek to exploit the autoregulatory (both inhibitory and activating) strategies employed by many kinases utilizing interactions with N- and C-terminal extensions or domains (like many RTKs with their juxtamembrane segments, or C-terminal tails), or with accessory factors, like cyclins for CDKs. Many of these docking interactions have been captured by a slew of X-ray structures, and have demonstrated allosteric effects-at-a-distance on the conformation and coordinate activity of the enzyme. Is it possible to improve on nature and design or select for a small molecule drug that can carry out the same effect when docked to the relevant pocket? In addition, to circumvent the promiscuity of the ATP-binding active site pocket, we are designing experimental methods to access the often-unused allosteric pocket in the N-terminal kinase lobe, with the hope of deriving more specific kinase-inhibiting compounds.
Cellular ADPR economy (immunology, cancer, development)
Enzymes that catalyze the precise addition of ADP-ribose tags to protein targets are known as ADPR-transferases or ARTs, and likewise, their opposing molecules (hydrolases that cleave off the tags) are ARHs. We are are interested in investigating the role of these enzymes as a novel regulatory system in the cell. A class of functionally — and in some cases, structurally-related enzymes are the PARPs and PARG molecules of the poly-ADPR cell regulatory system, and we are participating in a larger effort to therapeutically target these enzymes.
Developmental pathways (cancer)
Notch, Hedgehog and Wnt efforts are quite an active field of work at Genentech, and we working on several different fronts in the analysis of relevant protein structures and their interactions (both extra- and intracellular) along their signaling pathways. In an associated vein, we are quite interested in the mechanisms and componentry of primary (sensory) cilia that are quite intriguing cellular structures critically involved in a variety of signaling pathways---notably Hedgehog. We are working with Peter Jackson's lab in the structural and functional analyses of a large molecular machine called the BBSome (short for Bardet-Biedl syndrome) that is involved in the regulated translocation of receptor signaling complexes to the tip of cilia."