Tuning Insulin Receptor Signaling Using De Novodesigned Agonists Xinru Wang Sarah Cardoso Kai Cai Preetham Venkatesh Albert Hung Michelle Ng Catherine Hall Brian Coventry David S Lee Rishabh Chowhan Stacey Gerben Jie Li Weidong An Mara Hon Michael Gao Yacheng Liao Domenico Accili by Xinru Wang & Sarah Cardoso & Kai Cai & Preetham Venkatesh & Albert Hung & Michelle Ng & Catherine Hall & Brian Coventry & David S. Lee & Rishabh Chowhan & Stacey Gerben & Jie Li & Weidong An & Mara Hon & Michael Gao & Ya-cheng Liao & Domenico Accili &... instant download after payment.

Insulin binding induces conformational changes in the insulin receptor(IR) that activate the intracellular kinasedomain and the protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways, regulatingmetabolism and proliferation. We reasoned that designed agonists inducing different IR conformationalchanges might induce different downstream responses. We used de novo protein design to generate bindersfor individual IR extracellular domains and fused them in different orientations with different conformationalflexibility. We obtained a series of synthetic IR agonists that elicit a wide range of receptor autophosphorylation, MAPKactivation,trafficking, and proliferation responses. We identified designs more potent than insulin,causing longer-lasting glucose lowering in vivo and retaining activity on disease-causing IR mutants, whilelargely avoiding the cancer cell proliferation induced by insulin. Our findings shed light on how changes inIR conformation and dynamics translate into downstream signaling, and with further development, our synthetic agonists could have therapeutic utility for metabolic and proliferative diseases.