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

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
Pages23-40
Number of pages18
ISBN (Electronic)9789048129096
DOIs
Publication statusPublished - 1 Jan 2010

Fingerprint

Receptor Activity-Modifying Protein 1
Calcitonin Gene-Related Peptide Receptors
G-Protein-Coupled Receptors
Ligands
Calcitonin Receptor-Like Protein
Protein Binding
Proteins

Keywords

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

Cite this

Barwell, J., Simms, J., Conner, A., Hay, D., Wheatley, M., & Poyner, D. (2010). Ligand binding and activation of the CGRP receptor. In The Calcitonin Gene-related Peptide Family: Form, Function and Future Perspectives (pp. 23-40) https://doi.org/10.1007/978-90-481-2909-6_2
Barwell, James ; Simms, John ; Conner, Alex ; Hay, Debbie ; Wheatley, Mark ; Poyner, David. / Ligand binding and activation of the CGRP receptor. The Calcitonin Gene-related Peptide Family: Form, Function and Future Perspectives. 2010. pp. 23-40
@inbook{3bd88811f3fd47c6a4b5a2fd9185e341,
title = "Ligand binding and activation of the CGRP receptor",
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.",
keywords = "Alanine scan, CGRP binding, Family B GPCR, Molecular modelling, RAMP1, Receptor activation, Site-directed mutagenesis",
author = "James Barwell and John Simms and Alex Conner and Debbie Hay and Mark Wheatley and David Poyner",
year = "2010",
month = "1",
day = "1",
doi = "10.1007/978-90-481-2909-6_2",
language = "English",
isbn = "9789048129089",
pages = "23--40",
booktitle = "The Calcitonin Gene-related Peptide Family",

}

Barwell, J, Simms, J, Conner, A, Hay, D, Wheatley, M & Poyner, D 2010, Ligand binding and activation of the CGRP receptor. in The Calcitonin Gene-related Peptide Family: Form, Function and Future Perspectives. pp. 23-40. https://doi.org/10.1007/978-90-481-2909-6_2

Ligand binding and activation of the CGRP receptor. / Barwell, James; Simms, John; Conner, Alex; Hay, Debbie; Wheatley, Mark; Poyner, David.

The Calcitonin Gene-related Peptide Family: Form, Function and Future Perspectives. 2010. p. 23-40.

Research output: Chapter in Book/Report/Conference proceedingChapter

TY - CHAP

T1 - Ligand binding and activation of the CGRP receptor

AU - Barwell, James

AU - Simms, John

AU - Conner, Alex

AU - Hay, Debbie

AU - Wheatley, Mark

AU - Poyner, David

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

KW - Alanine scan

KW - CGRP binding

KW - Family B GPCR

KW - Molecular modelling

KW - RAMP1

KW - Receptor activation

KW - Site-directed mutagenesis

UR - http://www.scopus.com/inward/record.url?scp=79960985964&partnerID=8YFLogxK

UR - https://link.springer.com/chapter/10.1007%2F978-90-481-2909-6_2

U2 - 10.1007/978-90-481-2909-6_2

DO - 10.1007/978-90-481-2909-6_2

M3 - Chapter

SN - 9789048129089

SP - 23

EP - 40

BT - The Calcitonin Gene-related Peptide Family

ER -

Barwell J, Simms J, Conner A, Hay D, Wheatley M, Poyner D. Ligand binding and activation of the CGRP receptor. In The Calcitonin Gene-related Peptide Family: Form, Function and Future Perspectives. 2010. p. 23-40 https://doi.org/10.1007/978-90-481-2909-6_2