期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 35, 页码 11170-11175出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b04432
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资金
- CNRS
- Paris Diderot University
- grant Laboratoire d'Excellence (LabEx) DYNAMO from the French Ministry of Research
- grant Equipements d'Excellence (EQUIPEX) CACSICE from the French Ministry of Research
- French National Research Agency through the Investments for the Future (France-BioImaging) [ANR-10-INSB-04, ANR-13-BSV8-0006]
- Tres Grandes Infrastructures de Recherche for NMR [TGIR-RMN-THC Fr3050 CNRS]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV8-0006] Funding Source: Agence Nationale de la Recherche (ANR)
Mapping the conformational landscape of G protein-coupled receptors (GPCRs), and in particular how this landscape is modulated by the membrane environment, is required to gain a clear picture of how signaling proceeds. To this end, we have developed an original strategy based on solution-state nuclear magnetic resonance combined with an efficient isotope labeling scheme. This strategy was applied to a typical GPCR, the leukotriene B-4 receptor BLT2, reconstituted in a lipid bilayer. Because of this, we are able to provide direct evidence that BLT2 explores a complex landscape that includes four different conformational states for the unliganded receptor. The relative distribution of the different states is modulated by ligands and the sterol content of the membrane, in parallel with the changes in the ability of the receptor to activate its cognate G protein. This demonstrates a conformational coupling between the agonist and the membrane environment that is likely to be fundamental for GPCR signaling.
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