TLRs play central roles in innate immune defense against viral and bacterial infection. They recognize common patterns in a large number ofmicrobial molecules and initiate potent immune responses against them. My research group has determined the first crystal structures ofTLR-ligand complexes.
These structures have revealed the extraordinary diversity of TLR-ligand interactions. From our structural observations, we have proposed a mechanism for receptor activation: ligand binding to the extracellular domains of receptors induces dimerization of the intracellular domains, which initiates signaling inside the cell by recruiting adaptor proteins to the receptor. In order to prove this hypothesis, we are trying to determine structures of complete TLR signaling complexes containing extracellular ligands and intracellular signaling proteins using cryo-EM.
The second research focus of my lab is developing therapeutic antibodies targeting membrane receptors. Monoclonal antibodies are the larges groups of biological therapeutics.The successful development of therapeutic antibodies often requires generation of a selective and potent molecule,
humanization of sequences, affinity maturation, Fe engineering to modulate effector functions.
My lab is interested in determining large number of antibody structures in complex with their target proteins using a high speed cryo-EM method.
Based on these structures, we design amino acid sequences that can improve performance of the antibodies. Affinity, specificity, stability and manufacturability of antibodies can be improved by this "structure based antibody optimization process".