The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor

Laurence J. Miller, Maoqing Dong

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptidebound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure-activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.

Original languageEnglish (US)
Pages (from-to)154-158
Number of pages5
JournalBiochemical Society Transactions
Volume41
Issue number1
DOIs
StatePublished - Feb 1 2013

Keywords

  • GPCR (G-protein-coupled receptor)
  • Ligand binding
  • Receptor conformation

ASJC Scopus subject areas

  • Biochemistry

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