Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor

Laurence J Miller, Maoqing Dong, Kaleeckal G. Harikumar

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The secretin receptor is a prototypic member of family B G protein-coupled receptors that binds and responds to a linear 27-residue peptide natural ligand. The carboxyl-terminal region of this peptide assumes a helical conformation that occupies the peptide-binding cleft within the structurally complex disulphide-bonded amino-terminal domain of this receptor. The amino terminus of secretin is directed toward the core helical bundle domain of this receptor that seems to be structurally distinct from the analogous region of family A G protein-coupled receptors. This amino-terminal region of secretin is critical for its biological activity, to stimulate Gs coupling and the agonist-induced cAMP response. While the natural peptide ligand is known to span the two key receptor domains, with multiple residue-residue approximation constraints well established, the orientation of the receptor amino terminus relative to the receptor core helical bundle domain is still unclear. Fluorescence studies have established that the mid-region and carboxyl-terminal end of secretin are protected by the receptor peptide-binding cleft and the amino terminus of secretin is most exposed to the aqueous milieu as it is directed toward the receptor core, with the mid-region of the peptide becoming more exposed upon receptor activation. Like other family B peptide hormone receptors, the secretin receptor is constitutively present in a structurally specific homo-dimeric complex built around the lipid-exposed face of transmembrane segment four. This complex is important for facilitating G protein association and achieving the high affinity state of this receptor.

Original languageEnglish (US)
Pages (from-to)18-26
Number of pages9
JournalBritish Journal of Pharmacology
Volume166
Issue number1
DOIs
StatePublished - May 2012

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G-Protein-Coupled Receptors
Ligands
Peptides
Secretin
Peptide Receptors
GTP-Binding Proteins
Disulfides
secretin receptor
Fluorescence
Lipids

Keywords

  • family B GPCR
  • negative cooperativity
  • photoaffinity labelling
  • RAMPs
  • receptor dimerization
  • secretin receptor

ASJC Scopus subject areas

  • Pharmacology

Cite this

Ligand binding and activation of the secretin receptor, a prototypic family B G protein-coupled receptor. / Miller, Laurence J; Dong, Maoqing; Harikumar, Kaleeckal G.

In: British Journal of Pharmacology, Vol. 166, No. 1, 05.2012, p. 18-26.

Research output: Contribution to journalArticle

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