CGRPmut and AM primarily contact CLR, but key RAMP contacts are also formed (Tables S1 and S2). Two key features of the peptide-binding sites are a hydrophobic patch extending from the base of CLR loop 4 to loop 3 and a pocket extending from the base of CLR loop 4 to loop 2 and the RAMPs (Figure 2). The CLR W72 bulge, previously called the “Trp shelf” (ter Haar et al., 2010), demarcates patch and pocket. The patch comprises the Trp shelf, F92, F95, and Y124. The pockets comprise the Trp shelf, D70, G71, W121, T122, Y124, and RAMP1 W84 and P85 in the CGRP receptor (Figures 2A and 2B) or RAMP2 R97, E101, E105, and P112 in the AM1 receptor (Figures 2C and 2D). CGRPmut G33-A36 and AM S48-G51 form type II β-turns that contact CLR loop 4 in part via hydrogen bonds between the turn main chain and CLR S117, R119, and W121 side chains (Figures 2B and 2D). The β-turns enable the peptide C termini to occupy their respective pockets where their amide groups hydrogen bond with the CLR T122 main chain and their C-terminal residues pack against the Trp shelf, CLR G71, and RAMP1 W84 from the α2-α3 loop, which makes hydrophobic contact with CGRPmut F37 (Figures 2A and 2B), or RAMP2 R97, E101, and E105 from α2, which hydrogen bond with AM Y52 and K46 (Figures 2C and 2D). Prior to the β-turns CGRPmut V32 and AM I47 similarly contact the patch, but moving backward thence the peptides diverge in their interactions. CGRPmut T30 forms main chain- and side chain-mediated hydrogen bonds with CLR D94 on loop 3 and contacts the patch via its side chain methyl group (Figures 2A and 2B). The single helical turn in AM enables K46 to contact the Trp shelf and pack against AM Y52 and AM P43 and A42 contact the patch (Figures 2C and 2D). AM K38-A42 form a series of main chain-mediated hydrogen bonds with the main chain of CLR loop 3 and the side chains of D94 in loop 3 and T37 on α1 (Figure 2D). For the CGRPmut-bound structure, 94% of the solvent accessible surface area (ASA) of the ECD complex buried at the interface with the peptide is from CLR (478 Å2) and only 6% is from RAMP1 (29 Å2). More ASA is buried at the interface with AM, but the majority is still from CLR, 90% (781 Å2), whereas RAMP2 contributes only 10% (85 Å2).