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 journalArticle

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 (US)
Pages (from-to)5865-5868
Number of pages4
JournalAngewandte Chemie - International Edition
Volume55
Issue number19
DOIs
StatePublished - May 4 2016

Fingerprint

G-Protein-Coupled Receptors
Peptides
Proteins
Blueprints
Glucagon-Like Peptide 1
Insulin
Metabolites
Modulators
Glucose
Lighting
Molecules
Testing
Pharmaceutical Preparations
Glucagon-Like Peptide-1 Receptor

Keywords

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

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

Broichhagen, J., Johnston, N. R., Von Ohlen, Y., Meyer-Berg, H., Jones, B. J., Bloom, S. R., ... Hodson, D. J. (2016). Allosteric Optical Control of a Class B G-Protein-Coupled Receptor. Angewandte Chemie - International Edition, 55(19), 5865-5868. https://doi.org/10.1002/anie.201600957

Allosteric Optical Control of a Class B G-Protein-Coupled Receptor. / Broichhagen, Johannes; Johnston, Natalie R.; Von Ohlen, Yorrick; Meyer-Berg, Helena; Jones, Ben J.; Bloom, Stephen R.; Rutter, Guy A.; Trauner, Dirk; Hodson, David J.

In: Angewandte Chemie - International Edition, Vol. 55, No. 19, 04.05.2016, p. 5865-5868.

Research output: Contribution to journalArticle

Broichhagen, J, Johnston, NR, Von Ohlen, Y, Meyer-Berg, H, Jones, BJ, Bloom, SR, Rutter, GA, Trauner, D & Hodson, DJ 2016, 'Allosteric Optical Control of a Class B G-Protein-Coupled Receptor', Angewandte Chemie - International Edition, vol. 55, no. 19, pp. 5865-5868. https://doi.org/10.1002/anie.201600957
Broichhagen J, Johnston NR, Von Ohlen Y, Meyer-Berg H, Jones BJ, Bloom SR et al. Allosteric Optical Control of a Class B G-Protein-Coupled Receptor. Angewandte Chemie - International Edition. 2016 May 4;55(19):5865-5868. https://doi.org/10.1002/anie.201600957
Broichhagen, Johannes ; Johnston, Natalie R. ; Von Ohlen, Yorrick ; Meyer-Berg, Helena ; Jones, Ben J. ; Bloom, Stephen R. ; Rutter, Guy A. ; Trauner, Dirk ; Hodson, David J. / Allosteric Optical Control of a Class B G-Protein-Coupled Receptor. In: Angewandte Chemie - International Edition. 2016 ; Vol. 55, No. 19. pp. 5865-5868.
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