G protein-coupled receptors (GPCRs) are critical transduction gatekeepers for extracellular signals, which are involved in numerous physiological processes and disease pathogenesis. Structural determination of GPCRs aids the understanding of the molecular mechanism underlying agonist interaction and signal transduction, which holds potential for future therapeutic drug discovery. Recently, cryo-electron microscopy (cryo-EM) has become a powerful approach to solve GPCR-transducer complex structures.
The amylin receptors (AMYRs) is the primary target for the actions of neuroendocrine peptide amylin (Amy), a glucoregulatory and satiety-inducing hormone, which is protective against postprandial spikes in blood glucose and overeating. There are three AMYRs that are heterodimers of the calcitonin receptor (CTR) and receptor activity-modifying protein 1 (RAMP1, AMY1R), as well as RAMP2 or RAMP3 (AMY2R and AMY3R, respectively). However, the mechanistic basis for RAMP modulation of CTR phenotype is unclear. In this study, we report the cryo-EM structures of three AMYRs in complex with Amy and Gs at the sub-2.6 Å global resolution. These structures reveal distinctions in the primary orientation of the extracellular domain (ECDs) relative to the receptor core in the presence of RAMP, in comparison with the previously reported CTR structure with salmon calcitonin (sCT). Analysis of 3D variance dynamic information in cryo-EM data offers insights into the effect of RAMP modulation on the extent of mobility of the ECDs. This work enriches our understanding of mechanisms of AMYRs activation that is allosterically modulated by RAMPs.