K. Christopher Garcia, Ph.D.

Research

Cell-surface receptors represent the gateway through which the cell senses and responds to its environment. Most physiologically important processes are initiated by the interaction of cell-surface receptors with extracellular mediators. This recognition event is communicated across the membrane, resulting in activation of intracellular signal transduction cascades. Molecular insight into recognition and activation of receptors implicated in human disease could reveal new strategies, or better inform current strategies, for therapeutic intervention. Thematically, we are interested in shared receptors, such as cytokine and T-cell receptors, that differentially respond to multiple ligands in protein-protein interaction systems, which play central roles in immunology, cancer, infectious disease, cellular development, and differentiation. In addition to understanding basic aspects of receptor signaling and structural biology, we are also interested in the discovery of novel receptor ligands using protein engineering and translating these molecules to the clinic. We approach our studies using a range of methodologies from structural biology to cell signaling to in vivo models.

As an Innovation Fund investigator, K. Christopher Garcia, Ph.D., is teaming up with Jesse Bloom, Ph.D., to explore and exploit protein-protein recognition. Protein-protein interactions found in nature likely arose through a process of coevolution. This process is poorly understood, largely because existing analytical approaches can interrogate only one binding partner at a time. The Garcia lab recently developed a platform for coevolving two proteins within very large and diverse interface libraries for both partners. This platform enables both the deep study of protein-protein recognition and the engineering of protein-protein interactions that have practical utility as drugs or in biotechnology. Combining this coevolution platform with Bloom’s extensive expertise in predictive virology, the pair hopes to better understand protein binding as well as engineer antibodies that retain binding to their viral targets during evolution. The pair’s research could establish the utility of this coevolution platform for engineering proteins and test the innovative strategy of developing antibodies that are impervious to probable future mutations in SARS-CoV-2 or in cancers.