Ectodomain structures of the CGRP and AM receptors

Receptor activity-modifying proteins (RAMPs) 1-3, which are classified as type I transmembrane proteins, serve as the partner proteins of several family B GPCRs for physiologically active peptides, including the calcitonin receptor- like receptor (CLR). The properties of the GPCRs are defined by the RAMP and peptide ligand combination. The CLR•RAMP1 heterodimer functions mainly as the calcitonin gene-related peptide (CGRP) receptor, while the CLR•RAMP2 and CLR•RAMP3 heterodimers primarily function as the adrenomedullin 1 and adrenomedullin 2 (AM₁ and AM₂) receptors, respectively. The crystal structures of the RAMP1 and RAMP2 ectodomains exhibited three-helix bundles, and those of their complexes with the N-terminal extracellular domain of CLR revealed how the two ectodomains associate to form the CGRP and AM₁ receptors, respectively. On this structural framework, the various intermolecular interactions of CLR with RAMP1 and RAMP2 result in the distinct shapes of the putative ligand-binding sites, where several residues are uniquely presented. Therefore, the differences in the shapes and the presented residues of the binding sites determine the specificities of the receptors to either CGRP or AM. These structural features of the ectodomains are consistent with mutagenesis results, and are useful to further examine the binding modes of the peptide ligands to the full-length CGRP and AM₁ receptors.