Current Research
Structural Biology and Protein Engineering of Cell Surface Receptor Signaling

K. Christopher Garcia studies the structural, mechanistic, and functional aspects of receptor-ligand interactions that play important roles in mammalian biology and human disease. To do this, he blends traditional structural approaches with ligand engineering and discovery. His goal is to paint a detailed mechanistic picture – from the outside to the inside of a cell – of how ligand binding is structurally coupled to receptor activation, and to exploit this information to manipulate signaling with engineered ligands, potentially resulting in therapeutics.

Garcia’s laboratory focuses on “shared” receptors, sometimes referred to as “pleiotropic.” These are receptors that can be activated by several structurally diverse ligands, giving rise to unique and redundant signaling outcomes. Garcia’s team has described new paradigms for recognition and activation of a range of shared receptors involved in adaptive immunity, neural signaling, and development.

For example, the researchers have shown that the cytokine receptor gp130 cross-reacts with different ligands through a uniquely accommodating surface chemistry within its structurally rigid binding site. Garcia also has a long-standing interest in T cell recognition of the peptide-MHC (major histocompatibility complex). His team is now looking at the question of whether there is a coevolved, germline-derived recognition code between T cell receptors and MHC molecules.

Garcia’s structural studies have also provided a snapshot of how developmentally important Wnt proteins bind to the Frizzled family of receptors. Wnts have long been considered a potential drug target for cancers, and knowing their structure provides a huge advantage when trying to develop compounds that will bind to Wnts.

A growing interest in the Garcia lab is receptor “deorphanization,” or matching receptors to their ligands. Using proteomics, Garcia’s group has discovered many new receptor-ligand pairs in Drosophila melanogaster. One of these new receptor-ligand families, the DIP-DPR network, appears to play a major role in wiring of the fly brain. Garcia hopes to escalate this work to a genome-wide receptor deorphanization program.

This work is also supported by grants from the National Institutes of Health.

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