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.
Keywords: Receptor activity-modifying protein, calcitonin receptor-like receptor, adrenomedullin, calcitonin gene-related peptide,
neovascularization, migraine, antagonist, crystal structure.
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