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Receptor dimerization is a fundamental mechanism by which most cytokines and growth factors activate Type-I transmembrane receptors. Although previous studies have shown that ligand-induced topological changes in the extracellular domains (ECDs) of dimeric receptors can affect signaling output, the physiological relevance is not well understood. This is a difficult problem to study because an engineered ligand system does not exist that would enable a systematic exploration of the relationship between ligand-receptor dimer geometry and signaling. This question, as well as the capability of exploiting these structure-activity relationships for drug discovery, are important because most cytokines exert pleiotropic effects that limit their therapeutic utility. New approaches are needed to modulate cytokine signaling and identify clinically efficacious variants. By contrast, small-molecule ligands for G …