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Nat Commun. 2017 Feb 21;8:14505. doi: 10.1038/ncomms14505.

Membrane cholesterol access into a G-protein-coupled receptor.

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Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain.
Institut für Medizinische Physik und Biophysik, AG ProteiInformatics, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.
Department of Inorganic Chemistry, Organic Chemistry, and Biochemistry, Faculty of Science and Chemical Technologies and Faculty of Medicine of Ciudad Real. Regional Center of Biomedical Research (CRIB), University of Castilla-La Mancha (UCLM), 13071 Ciudad Real, Spain.
Department of Physics, Tampere University of Technology (TUT), PO Box 692, FI-33101 Tampere, Finland.
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, CZ-16610 Prague, Czech Republic.


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 A2A receptor (A2AR) 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 A2AR-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 A2AR interior in a biotinylation assay. Overall, we show that cholesterol's impact on A2AR-binding affinity goes beyond pure allosteric modulation and unveils a new interaction mode between cholesterol and the A2AR that could potentially apply to other GPCRs.

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