The structure of the CGRP and related receptors

John Simms, Sarah Routledge, Romez Uddin, David Poyner*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP–receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27–37 [D31,P34,F35] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR. Comparison with the crystal structure of a fragment of the allied peptide adrenomedullin bound to the ECD of CLR/RAMP2 confirms the importance of the interaction of the ligand C-terminus and the RAMP in determining pharmacology specificity, although the RAMPs probably also have allosteric actions. A cryo-electron microscope structure of calcitonin bound to the full-length CTR associated with Gs gives important clues as to the structure of the complete receptor and suggests that the N-terminus of CGRP makes contact with His5.40b, high on TM5 of CLR. However, it is currently not known how the RAMPs interact with the TM bundle of any GPCR. Major challenges remain in understanding how the ECD and TM domains work together to determine ligand specificity, and how G-proteins influence this and the role of RCP. It seems likely that allosteric mechanisms are particularly important as are the dynamics of the receptors.

Original languageEnglish
Title of host publicationHandbook of Experimental Pharmacology
EditorsS. Brain, P. Gepetti
PublisherSpringer
Pages23-36
Number of pages14
ISBN (Electronic)978-3-030-21454-8
ISBN (Print)978-3-030-21453-1
DOIs
Publication statusE-pub ahead of print - 25 May 2018

Publication series

NameHandbook of Experimental Pharmacology
Volume255
ISSN (Print)0171-2004
ISSN (Electronic)1865-0325

Fingerprint

Calcitonin Receptor-Like Protein
Calcitonin Gene-Related Peptide Receptors
Receptor Activity-Modifying Protein 1
Calcitonin Receptors
G-Protein-Coupled Receptors
Crystal structure
Ligands
Adrenomedullin
Peptide Fragments
Proteins
Calcitonin
GTP-Binding Proteins
Amides
Electron microscopes
Pharmacology
Electrons

Keywords

  • Allostery
  • Amylin
  • Calcitonin
  • Cryo-electron microscopy
  • Crystallography
  • Family B G-protein-coupled receptor
  • Molecular dynamics

Cite this

Simms, J., Routledge, S., Uddin, R., & Poyner, D. (2018). The structure of the CGRP and related receptors. In S. Brain, & P. Gepetti (Eds.), Handbook of Experimental Pharmacology (pp. 23-36). (Handbook of Experimental Pharmacology; Vol. 255). Springer. https://doi.org/10.1007/164_2018_132
Simms, John ; Routledge, Sarah ; Uddin, Romez ; Poyner, David. / The structure of the CGRP and related receptors. Handbook of Experimental Pharmacology. editor / S. Brain ; P. Gepetti. Springer, 2018. pp. 23-36 (Handbook of Experimental Pharmacology).
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Simms, J, Routledge, S, Uddin, R & Poyner, D 2018, The structure of the CGRP and related receptors. in S Brain & P Gepetti (eds), Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology, vol. 255, Springer, pp. 23-36. https://doi.org/10.1007/164_2018_132

The structure of the CGRP and related receptors. / Simms, John; Routledge, Sarah; Uddin, Romez; Poyner, David.

Handbook of Experimental Pharmacology. ed. / S. Brain; P. Gepetti. Springer, 2018. p. 23-36 (Handbook of Experimental Pharmacology; Vol. 255).

Research output: Chapter in Book/Report/Conference proceedingChapter

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T1 - The structure of the CGRP and related receptors

AU - Simms, John

AU - Routledge, Sarah

AU - Uddin, Romez

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N2 - The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP–receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27–37 [D31,P34,F35] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR. Comparison with the crystal structure of a fragment of the allied peptide adrenomedullin bound to the ECD of CLR/RAMP2 confirms the importance of the interaction of the ligand C-terminus and the RAMP in determining pharmacology specificity, although the RAMPs probably also have allosteric actions. A cryo-electron microscope structure of calcitonin bound to the full-length CTR associated with Gs gives important clues as to the structure of the complete receptor and suggests that the N-terminus of CGRP makes contact with His5.40b, high on TM5 of CLR. However, it is currently not known how the RAMPs interact with the TM bundle of any GPCR. Major challenges remain in understanding how the ECD and TM domains work together to determine ligand specificity, and how G-proteins influence this and the role of RCP. It seems likely that allosteric mechanisms are particularly important as are the dynamics of the receptors.

AB - The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP–receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27–37 [D31,P34,F35] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR. Comparison with the crystal structure of a fragment of the allied peptide adrenomedullin bound to the ECD of CLR/RAMP2 confirms the importance of the interaction of the ligand C-terminus and the RAMP in determining pharmacology specificity, although the RAMPs probably also have allosteric actions. A cryo-electron microscope structure of calcitonin bound to the full-length CTR associated with Gs gives important clues as to the structure of the complete receptor and suggests that the N-terminus of CGRP makes contact with His5.40b, high on TM5 of CLR. However, it is currently not known how the RAMPs interact with the TM bundle of any GPCR. Major challenges remain in understanding how the ECD and TM domains work together to determine ligand specificity, and how G-proteins influence this and the role of RCP. It seems likely that allosteric mechanisms are particularly important as are the dynamics of the receptors.

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KW - Family B G-protein-coupled receptor

KW - Molecular dynamics

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Simms J, Routledge S, Uddin R, Poyner D. The structure of the CGRP and related receptors. In Brain S, Gepetti P, editors, Handbook of Experimental Pharmacology. Springer. 2018. p. 23-36. (Handbook of Experimental Pharmacology). https://doi.org/10.1007/164_2018_132