RAMPs are an important class of accessory membrane proteins that modulate GPCR pharmacology. The CGRPmut-bound CLR:RAMP1 ECD and AM-bound CLR:RAMP2 ECD structures presented here expand our understanding of the mechanisms by which peptides can bind to class B GPCRs and increase our understanding of how RAMPs enable peptide selectivity. The engineered tethered ECD fusion proteins used for crystallization exhibited the same peptide selectivity rank order as the intact receptors, which indicated that they are valid reagents for studying selective peptide binding. The purified proteins bound their respective peptides with apparent affinities in the low μM range (Figures S1C, S1G, and S1H), which are lower than the affinities of the agonist peptides for intact receptors but typical for truncated peptides at class B GPCR ECDs (Pal et al., 2010; Parthier et al., 2007; Pioszak and Xu, 2008).