Molecular Cell
Volume 58, Issue 6, 18 June 2015, Pages 1040-1052
Journal home page for Molecular Cell

Article
Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor

https://doi.org/10.1016/j.molcel.2015.04.018Get rights and content
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Highlights

  • Crystal structures reveal how CGRP and AM peptides bind their heterodimeric receptors

  • CGRP and AM occupy a shared binding site on CLR with minimal contact to the RAMPs

  • Peptide binding modes were confirmed for intact receptors in cells by mutagenesis

  • Peptide selectivity arises from RAMP-specific contacts and subtle alteration of CLR

Summary

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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Present address: Adaptimmune Limited, 91 Park Drive, Milton Park, Abingdon, OX14 4RY, UK

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Present address: Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK