Structural basis of natural ligand binding and activation of the Class II G-protein-coupled secretin receptor

L. J. Miller, M. Dong, K. G. Harikumar, F. Gao

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The secretin receptor is prototypic of Class II GPCRs (G-protein-coupled receptors), based on its structural and functional characteristics and those of its natural agonist ligand. Secretin represents a linear 27-residue peptide with diffuse pharmacophoric domain. The secretin receptor includes the typical signature sequences for this receptor family within its predicted transmembrane segments and the highly conserved six cysteine residues contributing to three intradomain disulfide bonds within its long N-terminus. This domain is critical for secretin binding based on receptor mutagenesis and photoaffinity labelling studies. Full agonist analogues of secretin incorporating a photolabile moiety at various positions throughout the pharmacophore covalently label residues within this region, while only N-terminal probes have labelled the core helical bundle domain. Combining insights coming from receptor structural studies, peptide structure-activity relationship considerations, photoaffinity labelling, and application of fluorescence techniques has resulted in the development of a working model of the secretin-receptor complex. This supports the initial docking of the peptide agonist within a cleft in the receptor N-terminus, providing the opportunity for an endogenous sequence within that domain to interact with the core of the receptor. This interaction is believed to be key in the molecular basis of conformational change associated with activation of this receptor. The site of action of this endogenous agonist could also provide a possible target for small molecule agonists to act.

Original languageEnglish (US)
Pages (from-to)709-712
Number of pages4
JournalBiochemical Society Transactions
Volume35
Issue number4
DOIs
StatePublished - Aug 2007

Keywords

  • G-protein-coupled receptor (GPCR)
  • Ligand binding
  • Mutagenesis
  • Photoaffinity labelling
  • Receptor activation
  • Secretin receptor

ASJC Scopus subject areas

  • Biochemistry

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