Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14505
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Funding
- Fundacio La Marato de TV3 [091010]
- Instituto de Salud Carlos III FEDER [CP12/03139, PI15/00460]
- GLISTEN European Research Network
- Ministerio de Educacion y Ciencia [SAF2009-13609-C04-04]
- H2020 Project MedBioinformatics [634143]
- Deutsche Forschungsgemeinschaft [DFG HI 1502/1-1, WO 1908/2-1, SFB 740, SFB70]
- Norddeutscher Verbund fur Hoch-und Hochstleistungsrechner (HLRN)
- Ministerio de Economia y Competitividad [BFU2011-23034]
- JCCM [PEII-2014-030-P]
- AGAUR
- European Social Fund [2015 FI_B00145]
- Academy of Finland
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Cholesterol is a key component of cell membranes with a proven modulatory role on the function and ligand-binding properties of G-protein-coupled receptors (GPCRs). Crystal structures of prototypical GPCRs such as the adenosine A(2A) receptor (A(2A)R) have confirmed that cholesterol finds stable binding sites at the receptor surface suggesting an allosteric role of this lipid. Here we combine experimental and computational approaches to show that cholesterol can spontaneously enter the A(2A)R-binding pocket from the membrane milieu using the same portal gate previously suggested for opsin ligands. We confirm the presence of cholesterol inside the receptor by chemical modification of the A(2A)R interior in a biotinylation assay. Overall, we show that cholesterol's impact on A(2A)R-binding affinity goes beyond pure allosteric modulation and unveils a new interaction mode between cholesterol and the A(2A)R that could potentially apply to other GPCRs.
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