The calcitonin gene-related peptide (CGRP) receptor is a heterodimer of two 
membrane proteins: calcitonin receptor-like receptor (CLR) and receptor 
activity-modifying protein 1 (RAMP1). CLR is a class B G-protein-coupled 
receptor (GPCR), possessing a characteristic large amino-terminal extracellular 
domain (ECD) important for ligand recognition and binding. Dimerization of CLR 
with RAMP1 provides specificity for CGRP versus related agonists. Here we report 
the expression, purification, and refolding of a soluble form of the CGRP 
receptor comprising a heterodimer of the CLR and RAMP1 ECDs. The extracellular 
protein domains corresponding to residues 23-133 of CLR and residues 26-117 of 
RAMP1 were shown to be sufficient for formation of a stable, monodisperse 
complex. The binding affinity of the purified ECD complex for the CGRP peptide 
was significantly lower than that of the native receptor (IC(50) of 12 microM 
for the purified ECD complex vs 233 pM for membrane-bound CGRP receptor), 
indicating that other regions of CLR and/or RAMP1 are important for peptide 
agonist binding. However, high-affinity binding to known potent and specific 
nonpeptide antagonists of the CGRP receptor, including olcegepant and 
telcagepant (K(D) < 0.02 muM), as well as N-terminally truncated peptides and 
peptide analogues (140 nM to 1.62 microM) was observed.