1. Structure based pharmacology

    Using atomic data on drug targets to develop new cancer and immunology drugs. We are collaborating with Eureka Therapeutics and Dr. David Scheinberg at Memorial Sloan-Kettering Cancer Center to structurally characterize antibody therapeutics to better understand their mechanism of action and help engineer superior next generation antibodies against such targets as the ROR2 tyrosine kinase receptor and HLA-Wilms Tumor 1 peptide complex, which has recently demonstrated dramatic efficacy in leukemia in mice. A second focus is anti-estrogen drugs, which are important for treating breast cancer. We are investigating new mechanisms of targeting aromatase, the enzyme responsible for estrogen biosynthesis, for breast cancer. We are developing immunomodulatory drugs that inhibitor or activate the key immune switch, RORgamma, for the treatment of autoimmune disorders and cancer. Finally, in collaboration with Dr. James Turkson of the University of Hawaii Cancer Center, we are working towards crystallizing the transcription factor Stat3 with small molecule inhibitors. Stat3 is an important target for breast and other cancers. Structural information will help us design superior Stat3 drugs with higher binding affinity and selectivity. Our X-ray experiments are performed at state of the art, particle accelerator facilities such as the Stanford Synchrotron Radiation Lightsource and the Advanced Light Source.

ESK1 antibody bount to HLA receptor

Crystal structure of Stat3 transcription factor

2. Membrane protein structure and proteomics

     Identifying optimal membrane protein candidates for crystallization. Membrane proteins are more than half of all known drug targets. However, they have been notoriously difficult to crystallize, constituting less than 1% of all known protein crystal structures. We are developing a new strategy to pre-select membrane proteins that are most likely to crystallize. We are identifying membrane proteins that are both heat stable and monodisperse in detergent by mass spectrometry from bacteria and higher eukaryotes. We are in the process of cloning and expressing these membrane proteins for crystallization trials. This research will accelerate fundamental understanding of membrane protein structure. This is a collaboration with the Keck Proteomics Lab at Yale.

Mass spectrometry and proteomics

3. Hydrogen atoms in protein structure and function

     Detecting invisible hydrogen atoms in proteins. We are developing a new computational method, HyPO (Hydrogen atom Prediction and Observation) for analyzing protein X-ray crystallography maps to detect hydrogen atoms. Hydrogen atoms, having only one electron, scatter X-rays very weakly and are often invisible in X-ray maps. HyPO locates hydrogen atoms, which play critical roles in protein function such as enzyme mechanism and ligand binding. We are developing HyPO to work with x-ray crystallography maps of modest resolution and weak neutron crystallography maps. HyPO predictions will be tested experimentally by x-ray and neutron crystallography. Neutron crystallography is performed in collaboration with colleagues at Oak Ridge National Laboratory.

Locating hydrogen atoms from neutron crystallography
Identification of hydrogen atoms by analysis of crystallography electron density maps

4. Protein engineering and design

     Transforming proteins with new functions. Atomic level understanding of proteins allows us to re-engineer natural proteins to adopt new, useful functions. The design of new structures and functions is also the ultimate experimental test of the limits of our knowledge and technology. We are engineering improved versions of naturally occurring human enzymes for therapeutic use against cancer. Also, in collaboration with Dr. Michael Lin of Stanford, we are helping to develop new fluorescent proteins with improved spectral properties, that can act as biosensors and optical switches. Through crystallographic and computational methods, we are developing theories of chemical mechanisms that can guide the development of fluorescent proteins with improved brightness and spectral properties.

red fluorescent protein Neptune crystal structure