In summary, the structures presented here provide the first structural views of any accessory membrane protein modulating GPCR ligand binding and may provide a basis for understanding modulation of other GPCRs by accessory proteins. Our data indicate that RAMPs determine peptide selectivity of CLR through a combination of binding site augmentation and alteration of CLR conformation. It is striking that relatively minor differences in RAMP-specific peptide contacts and subtle RAMP-induced changes in CLR conformation lead to such profoundly different pharmacological profiles. Of practical value, the structures may inform rational drug design targeting CLR:RAMP complexes with clinical relevance for migraine headache and cardiovascular disorders. Lastly, the MBP-tethered ECD fusion protein approach to crystallization should facilitate structural studies of other CT family peptides bound to their respective receptor ECD complexes, which will enable a more complete understanding of how RAMPs modulate both CLR and CTR.