Allosteric optical control of a class B G-protein-coupled receptor

Johannes Broichhagen, Natalie R. Johnston, Yorrick Von Ohlen, Helena Meyer-berg, Ben J. Jones, Stephen R. Bloom, Guy A. Rutter, Dirk Trauner, David J. Hodson

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)
158 Downloads (Pure)

Abstract

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon-like peptide-1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small-molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.
Original languageEnglish
Pages (from-to)5865–5868
Number of pages4
JournalAngewandte Chemie (International Edition)
Volume55
Issue number19
Early online date5 Apr 2016
DOIs
Publication statusPublished - 4 May 2016

Keywords

  • allosteric regulation
  • beta cells
  • GLP-1 receptor
  • photopharmacology
  • type 2 diabetes

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