Focal Point (Left to right) Ünal Coskun, Theresia Gutmann, Kelly Kim, Thomas Walz, and (not pictured) Michal Grzybek perform single-particle electron microscopy on full-length human insulin receptors embedded in lipid nanodiscs and identify an insulin-induced conformational shift that brings together the receptor’s intracellular kinase domains, enabling autophosphorylation and receptor activation. In the absence of insulin (left), the dimeric receptor’s ectodomain adopts an inverted U-shape that separates the two transmembrane domains. In the presence of insulin (right), the ectodomain converts to a T-shaped conformation, bringing the receptor’s transmembrane and intracellular domains together.  Coskun and Gutmann photo courtesy of Franziska Clauß. Walz and Kim photos courtesy of the authors.