Abstract
The second extracellular loop (ECL2) of the G protein-coupled receptor (GPCR) family is important for ligand interaction and drug discovery. ECL2 of the family B cardioprotective calcitonin gene-related peptide (CGRP) receptor is required for cell signaling. Family B GPCR ligands have two regions; the N-terminus mediates receptor activation, and the remainder confers high-affinity binding. Comparing antagonism of CGRP8-37 at a number of point mutations of ECL2 of the CGRP receptor, we show that the ECL2 potentially facilitates interaction with up to the 18 N-terminal residues of CGRP. This has implications for understanding family B GPCR activation and for drug design at the CGRP receptor.
MeSH terms
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Amino Acid Substitution
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Animals
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Binding Sites
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Binding, Competitive
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COS Cells
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Calcitonin Gene-Related Peptide / chemistry
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Calcitonin Gene-Related Peptide / genetics
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Calcitonin Gene-Related Peptide / metabolism
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Calcitonin Gene-Related Peptide / pharmacology*
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Calcitonin Receptor-Like Protein / agonists*
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Calcitonin Receptor-Like Protein / chemistry
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Calcitonin Receptor-Like Protein / genetics
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Calcitonin Receptor-Like Protein / metabolism
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Chlorocebus aethiops
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Kinetics
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Ligands
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Miotics / chemistry
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Miotics / metabolism
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Miotics / pharmacology*
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Models, Molecular*
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Peptide Fragments / pharmacology*
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Point Mutation
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Protein Conformation
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Protein Interaction Domains and Motifs
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Protein Interaction Mapping
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Protein Multimerization
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Receptor Activity-Modifying Protein 1 / chemistry
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Receptor Activity-Modifying Protein 1 / genetics
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Receptor Activity-Modifying Protein 1 / metabolism*
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Receptors, Calcitonin Gene-Related Peptide / agonists*
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Receptors, Calcitonin Gene-Related Peptide / chemistry
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Receptors, Calcitonin Gene-Related Peptide / genetics
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Receptors, Calcitonin Gene-Related Peptide / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects*
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Structural Homology, Protein
Substances
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CALCRL protein, human
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CRCP protein, human
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Calcitonin Receptor-Like Protein
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Ligands
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Miotics
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Peptide Fragments
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RAMP1 protein, human
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Receptor Activity-Modifying Protein 1
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Receptors, Calcitonin Gene-Related Peptide
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Recombinant Proteins
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calcitonin gene-related peptide (8-37)
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Calcitonin Gene-Related Peptide