Allosteric Optical Control of a Class B G-Protein-Coupled Receptor

被引：41

作者：

Broichhagen, Johannes ^{[1
,2
,3
]}

Johnston, Natalie R. ^{[4
]}

von Ohlen, Yorrick ^{[4
]}

Meyer-Berg, Helena ^{[1
,2
]}

Jones, Ben J. ^{[5
]}

Bloom, Stephen R. ^{[5
]}

Rutter, Guy A. ^{[4
]}

Trauner, Dirk ^{[1
,2
]}

Hodson, David J. ^{[4
,6
,7
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Dept Chem, Butenandtstr 5-13, D-81377 Munich, Germany

[2] Ludwig Maximilians Univ Munchen, Ctr Integrated Prot Sci CIPSM, Butenandtstr 5-13, D-81377 Munich, Germany

[3] Ecole Polytech Fed Lausanne, Inst Chem Sci & Engn ISIC, Lab Prot Engn LIP, CH-1015 Lausanne, Switzerland

[4] Univ London Imperial Coll Sci Technol & Med, Sect Cell Biol & Funct Genom, Div Diabet Endocrinol & Metab, Dept Med,Hammersmith Hosp, Du Cane Rd, London W12 0NN, England

[5] Univ London Imperial Coll Sci Technol & Med, Sect Invest Med, Div Diabet Endocrinol & Metab, London W12 0NN, England

[6] Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England

[7] Birmingham Hlth Partners, Ctr Endocrinol Diabet & Metab, Birmingham B15 2TH, W Midlands, England

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2016年 / 55卷 / 19期

基金：

英国生物技术与生命科学研究理事会; 欧洲研究理事会; 英国惠康基金;

关键词：

allosteric regulation; beta cells; GLP-1; receptor; photopharmacology; type2; diabetes; PANCREATIC BETA-CELLS; INSULIN-SECRETION; MODULATION; ACTIVATION; MECHANISMS;

D O I：

10.1002/anie.201600957

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 classB 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 classB GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.

引用

页码：5865 / 5868

页数：4

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