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Tuning receptor signaling through ligand engineering

I will present the results of studies in our laboratory investigating the role of extracellular ligand‐receptor complex structure on the nature of signaling outputs in a range of systems. Most cell surface receptors are activated by some degree of ligand‐mediated clustering or oligomerization, but it is less clear to what degree the nature of the downstream signal induced by ligand can be ‘tuned’ or manipulated by natural or engineered ligands that engage the receptors with alternative geometries or binding parameters. Typically, ligands that elicit distinct pharmacologies through a single receptor have been observed GPCRs, but we have engineered ligands for T cell and cytokine receptors that exhibit partial agonism and inverse agonism. As one example, we have modulated cytokine receptor signaling by altering the orientation and proximity of a cytokine receptor dimer using diabodies and other synthetic designed scaffolds as surrogate ligands. We directly correlated the intact receptor dimer structures, determined crystallographically, with functional outcome and we find that indeed such systems are ‘tunable’ by remodeling dimer topology and distance. Thus, induced alterations in receptor dimer geometry can ‘tune’ signaling and extracellular ligands that enforce large receptor inter‐subunit distances can counteract intracellular oncogenic ligand‐independent receptor activation. The approach of modulating signaling output through receptors is important to overcoming the therapeutic limitations of cytokine pleiotropy. In my talk I will discuss recent results bearing on this topic.