Ligand binding and activation of the CGRP receptor

James Barwell, John Simms, Alex Conner, Debbie Hay, Mark Wheatley, David Poyner

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

The CGRP receptor is an atypical G-protein coupled receptor (GPCR), consisting of at least three proteins; a Family-B GPCR (calcitonin receptor-like receptor; CLR or CRLR), receptor activity modifying protein 1 (RAMP1) and receptor component protein (RCP). The extracellular domain of RAMP1 is tri-helical and possibly interacts with the extreme N-terminus of CLR to form the functional receptor. CGRP binding probably follows a two-step model of activation. The C-terminus of CGRP interacts with the N-terminus of the CLR/RAMP1 complex and its N-terminus interacts with the extracellular loops and of CLR to cause activation. The second and third extracellular loops are particularly important. During receptor activation TM helices 3 and 6 probably move apart. P343 in TM 6 is particularly important; E233 in TM3 and R173 and/or H178 in TM2 may form intermolecular interactions that may mirror the function of the DRY motif found in Family A GPCRs. Upon receptor activation the intracellular loops move to create a Gs-protein binding pocket.

Original languageEnglish
Title of host publicationThe Calcitonin Gene-related Peptide Family
Subtitle of host publicationForm, Function and Future Perspectives
EditorsDeborah L. Hay, Ian M. Dickerson
Place of PublicationNetherlands
PublisherSpringer Verlag
Pages23-40
Number of pages18
Edition1
ISBN (Electronic)9789048129096
ISBN (Print)9789048129089, 9789400791800
DOIs
Publication statusPublished - 2010
Externally publishedYes

Keywords

  • Alanine scan
  • CGRP binding
  • Family B GPCR
  • Molecular modelling
  • RAMP1
  • Receptor activation
  • Site-directed mutagenesis

ASJC Scopus subject areas

  • Medicine(all)

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