Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor |
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| Authors: | Dr Johannes Broichhagen Natalie R Johnston Yorrick von Ohlen Helena Meyer‐Berg Dr Ben J Jones Prof Dr Stephen R Bloom Prof Dr Guy A Rutter Prof Dr Dirk Trauner Dr David J Hodson |
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| Institution: | 1. LMU Munich, Department of Chemistry and Center for Integrated Protein Science (CIPSM), Munich, Germany;2. école Polytechnique Fédérale de Lausanne (EPFL), Institute of Chemical Sciences and Engineering (ISIC), Laboratory of Protein Engineering (LIP), Lausanne, Switzerland;3. Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, London, UK;4. Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, UK;5. Institute of Metabolism and Systems Research (IMSR), University of Birmingham, UK;6. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK |
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| 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. |
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| Keywords: | allosteric regulation beta cells GLP-1 receptor photopharmacology type 2 diabetes |
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