Interfacial Binding Sites for Cholesterol on G Protein-Coupled Receptors
- PMID: 31010663
- PMCID: PMC6506644
- DOI: 10.1016/j.bpj.2019.03.025
Interfacial Binding Sites for Cholesterol on G Protein-Coupled Receptors
Abstract
A docking procedure is described that allows the transmembrane surface of a G protein-coupled receptor (GPCR) to be swept rapidly for potential binding sites for cholesterol at the bilayer interfaces on the two sides of the membrane. The procedure matches 89% of the cholesterols resolved in published GPCR crystal structures, when cholesterols likely to be crystal packing artifacts are excluded. Docking poses are shown to form distinct clusters on the protein surface, the clusters corresponding to "greasy hollows" between protein ridges. Docking poses depend on the angle of tilt of the GPCR in the surrounding lipid bilayer. It is suggested that thermal motion could alter the optimal binding pose for a cholesterol molecule, with the range of binding poses within a cluster providing a guide to the range of thermal motions likely for a cholesterol within a binding site.
Copyright © 2019 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Figures








Similar articles
-
Interfacial Binding Sites for Cholesterol on TRP Ion Channels.Biophys J. 2019 Nov 19;117(10):2020-2033. doi: 10.1016/j.bpj.2019.10.011. Epub 2019 Oct 18. Biophys J. 2019. PMID: 31672270 Free PMC article.
-
G protein coupled receptor interactions with cholesterol deep in the membrane.Biochim Biophys Acta Biomembr. 2017 Feb;1859(2):268-281. doi: 10.1016/j.bbamem.2016.12.001. Epub 2016 Dec 3. Biochim Biophys Acta Biomembr. 2017. PMID: 27919726
-
Assessing GPCR homology models constructed from templates of various transmembrane sequence identities: Binding mode prediction and docking enrichment.J Mol Graph Model. 2018 Mar;80:38-47. doi: 10.1016/j.jmgm.2017.12.017. Epub 2017 Dec 29. J Mol Graph Model. 2018. PMID: 29306746
-
Molecular dynamics simulations of GPCR-cholesterol interaction: An emerging paradigm.Biochim Biophys Acta. 2015 Sep;1848(9):1775-82. doi: 10.1016/j.bbamem.2015.03.018. Epub 2015 Mar 25. Biochim Biophys Acta. 2015. PMID: 25817549 Review.
-
Are specific nonannular cholesterol binding sites present in G-protein coupled receptors?Biochim Biophys Acta. 2009 Feb;1788(2):295-302. doi: 10.1016/j.bbamem.2008.11.020. Epub 2008 Dec 9. Biochim Biophys Acta. 2009. PMID: 19111523 Review.
Cited by
-
Local Enrichment of Unsaturated Chains around the A2A Adenosine Receptor.Biochemistry. 2019 Oct 1;58(39):4096-4105. doi: 10.1021/acs.biochem.9b00607. Epub 2019 Sep 19. Biochemistry. 2019. PMID: 31496229 Free PMC article.
-
Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1.J Phys Chem B. 2024 Sep 5;128(35):8437-8447. doi: 10.1021/acs.jpcb.4c02828. Epub 2024 Aug 22. J Phys Chem B. 2024. PMID: 39169808 Free PMC article.
-
Exploring TRPC3 Interaction with Cholesterol through Coarse-Grained Molecular Dynamics Simulations.Biomolecules. 2022 Jun 25;12(7):890. doi: 10.3390/biom12070890. Biomolecules. 2022. PMID: 35883446 Free PMC article.
-
Cholesterol in Class C GPCRs: Role, Relevance, and Localization.Membranes (Basel). 2023 Mar 3;13(3):301. doi: 10.3390/membranes13030301. Membranes (Basel). 2023. PMID: 36984688 Free PMC article.
-
Bayesian Nonparametric Analysis of Residence Times for Protein-Lipid Interactions in Molecular Dynamics Simulations.J Chem Theory Comput. 2025 Apr 22;21(8):4203-4220. doi: 10.1021/acs.jctc.4c01522. Epub 2025 Apr 2. J Chem Theory Comput. 2025. PMID: 40172093
References
-
- Gimpl G. Interaction of G protein coupled receptors and cholesterol. Chem. Phys. Lipids. 2016;199:61–73. - PubMed
-
- Simmonds A.C., East J.M., Lee A.G. Annular and non-annular binding sites on the (Ca2+ + Mg2+)-ATPase. Biochim. Biophys. Acta. 1982;693:398–406. - PubMed
-
- Lee A.G. How lipids affect the activities of integral membrane proteins. Biochim. Biophys. Acta. 2004;1666:62–87. - PubMed
-
- Lee A.G. Biological membranes: the importance of molecular detail. Trends Biochem. Sci. 2011;36:493–500. - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical