title: Allosteric Optical Control of a Class B G-Protein-Coupled Receptor.
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 Ca(2+) , 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.
authors.affiliation: LMU Munich, Department of Chemistry and Center for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377, Munich, Germany.|École Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering (ISIC), Laboratory of Protein Engineering (LIP), 1015, Lausanne, Switzerland.
authors.forename: Johannes
authors.identifier: 0000-0003-3084-6595
authors.initials: J
authors.lastname: Broichhagen
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Johnston
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Yorrick
authors.initials: Y
authors.lastname: von Ohlen
authors.affiliation: LMU Munich, Department of Chemistry and Center for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377, Munich, Germany.
authors.forename: Helena
authors.identifier: 0000-0001-6435-7584
authors.initials: H
authors.lastname: Meyer-Berg
authors.affiliation: Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, UK.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Jones
authors.affiliation: Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: LMU Munich, Department of Chemistry and Center for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377, Munich, Germany. dirk.trauner@lmu.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. d.hodson@imperial.ac.uk, d.hodson@bham.ac.uk.|Institute of Metabolism and Systems Research (IMSR), University of Birmingham, B15 2TT, UK. d.hodson@imperial.ac.uk, d.hodson@bham.ac.uk.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, B15 2TH, UK. d.hodson@imperial.ac.uk, d.hodson@bham.ac.uk.
authors.forename: David J
authors.identifier: 0000-0002-8641-8568
authors.initials: DJ
authors.lastname: Hodson
mesh_terms: D000494:Allosteric Regulation / Q000528:radiation effects; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007536:Isomerism; D008027:Light; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D014466:Ultraviolet Rays
chemical_list: C570819:4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine; D000814:Aniline Compounds; D001391:Azo Compounds; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; C000627983:PhotoETP; D011743:Pyrimidines; D000242:Cyclic AMP; C009850:azobenzene; D002118:Calcium
keywords: GLP-1 receptor; allosteric regulation; beta cells; photopharmacology; type 2 diabetes