Structural insight into selectivity of amylin and calcitonin receptor agonists

Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a ‘bypass’ secondary structural motif (residues S19–P25). This study explored potential tuning of peptide selectivity through modification to residues 19–22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMY3R, and San45 bound to AMY3R or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMY3R. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects. Cryo-EM structure and dynamics analysis provides a conformational mechanism for tuning of selectivity between calcitonin and amylin receptors through targeted lipid modification of residues 19–22 within the ‘bypass’ motif of amylin peptides.