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

Jason M Booe, Christopher S Walker, James Barwell, Gabriel Kuteyi, John Simms, Muhammad A Jamaluddin, Margaret L Warner, Roslyn M Bill, Paul W Harris, Margaret A Brimble, David R Poyner, Debbie L Hay, Augen A Pioszak

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1040-52
Number of pages13
JournalMolecular Cell
Volume58
Issue number6
DOIs
Publication statusPublished - 18 Jun 2015
Externally publishedYes

Keywords

  • Adrenomedullin
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • COS Cells
  • Calcitonin Gene-Related Peptide
  • Calcitonin Receptor-Like Protein
  • Cercopithecus aethiops
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Peptides
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor Activity-Modifying Protein 1
  • Receptor Activity-Modifying Protein 2
  • Sequence Homology, Amino Acid
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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  • Cite this

    Booe, J. M., Walker, C. S., Barwell, J., Kuteyi, G., Simms, J., Jamaluddin, M. A., ... Pioszak, A. A. (2015). Structural Basis for Receptor Activity-Modifying Protein-Dependent Selective Peptide Recognition by a G Protein-Coupled Receptor. Molecular Cell, 58(6), 1040-52. https://doi.org/10.1016/j.molcel.2015.04.018