Predictions for Cholesterol Interaction Sites on the A2A Adenosine Receptor

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2012 Sep 26

PMID 23005256

Citations 52

Authors

Ji Young Lee

Edward Lyman

Affiliations

Soon will be listed here.

Abstract

Molecular dynamics simulations of the A(2A) adenosine receptor totaling 1.4 μs show clear evidence for specific sites mediating interactions between adenosine-bound A(2A) and cholesterol. The strongest evidence is for three binding sites. Two are in the extracellular leaflet, with one site interacting with helices VII and I, and the other with helices II and III. One site is located in the intracellular leaflet, interacting with helices III and IV. One of our three predicted binding sites is confirmed by a just-published high-resolution structure of A(2A) cocrystallized with an antagonist.

Citing Articles

Low Density Lipoprotein Cholesterol Decreases the Expression of Adenosine A Receptor and Lipid Rafts-Protein Flotillin-1: Insights on Cardiovascular Risk of Hypercholesterolemia.

Chaptal M, Maraninchi M, Musto G, Mancini J, Chtioui H, Dupont-Roussel J Cells. 2024; 13(6.

PMID: 38534331 PMC: 10969546. DOI: 10.3390/cells13060488.

Estimating the Cholesterol Affinity of Integral Membrane Proteins from Experimental Data.

Steck T, Tabei S, Lange Y Biochemistry. 2023; 63(1):19-26.

PMID: 38099740 PMC: 10765374. DOI: 10.1021/acs.biochem.3c00567.

Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the A Adenosine Receptor.

Tzortzini E, Kolocouris A Biomolecules. 2023; 13(6).

PMID: 37371538 PMC: 10296092. DOI: 10.3390/biom13060957.

Applications of Molecular Dynamics Simulation in Protein Study.

Sinha S, Tam B, Wang S Membranes (Basel). 2022; 12(9).

PMID: 36135863 PMC: 9505860. DOI: 10.3390/membranes12090844.

Regulation of membrane protein structure and function by their lipid nano-environment.

Levental I, Lyman E Nat Rev Mol Cell Biol. 2022; 24(2):107-122.

PMID: 36056103 PMC: 9892264. DOI: 10.1038/s41580-022-00524-4.

References

Hino T, Arakawa T, Iwanari H, Yurugi-Kobayashi T, Ikeda-Suno C, Nakada-Nakura Y . G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody. Nature. 2012; 482(7384):237-40. PMC: 3303121. DOI: 10.1038/nature10750. View

Pucadyil T, Chattopadhyay A . Role of cholesterol in the function and organization of G-protein coupled receptors. Prog Lipid Res. 2006; 45(4):295-333. DOI: 10.1016/j.plipres.2006.02.002. View

Liu W, Chun E, Thompson A, Chubukov P, Xu F, Katritch V . Structural basis for allosteric regulation of GPCRs by sodium ions. Science. 2012; 337(6091):232-6. PMC: 3399762. DOI: 10.1126/science.1219218. View

Khelashvili G, Grossfield A, Feller S, Pitman M, Weinstein H . Structural and dynamic effects of cholesterol at preferred sites of interaction with rhodopsin identified from microsecond length molecular dynamics simulations. Proteins. 2009; 76(2):403-17. PMC: 4101808. DOI: 10.1002/prot.22355. View

van Meer G, Voelker D, Feigenson G . Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008; 9(2):112-24. PMC: 2642958. DOI: 10.1038/nrm2330. View

Pan J, Mills T, Tristram-Nagle S, Nagle J . Cholesterol perturbs lipid bilayers nonuniversally. Phys Rev Lett. 2008; 100(19):198103. PMC: 2695669. DOI: 10.1103/PhysRevLett.100.198103. View

Jaakola V, Griffith M, Hanson M, Cherezov V, Chien E, Lane J . The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science. 2008; 322(5905):1211-7. PMC: 2586971. DOI: 10.1126/science.1164772. View

Gimpl G, Burger K, Fahrenholz F . Cholesterol as modulator of receptor function. Biochemistry. 1997; 36(36):10959-74. DOI: 10.1021/bi963138w. View

Yao Z, Kobilka B . Using synthetic lipids to stabilize purified beta2 adrenoceptor in detergent micelles. Anal Biochem. 2005; 343(2):344-6. DOI: 10.1016/j.ab.2005.05.002. View

10.

Simons K, Ikonen E . How cells handle cholesterol. Science. 2000; 290(5497):1721-6. DOI: 10.1126/science.290.5497.1721. View

11.

Ruprecht J, Mielke T, Vogel R, Villa C, Schertler G . Electron crystallography reveals the structure of metarhodopsin I. EMBO J. 2004; 23(18):3609-20. PMC: 517614. DOI: 10.1038/sj.emboj.7600374. View

12.

Lee J, Lyman E . Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor. Biophys J. 2012; 102(9):2114-20. PMC: 3341534. DOI: 10.1016/j.bpj.2012.03.061. View

13.

Jafurulla M, Tiwari S, Chattopadhyay A . Identification of cholesterol recognition amino acid consensus (CRAC) motif in G-protein coupled receptors. Biochem Biophys Res Commun. 2010; 404(1):569-73. DOI: 10.1016/j.bbrc.2010.12.031. View

14.

Xu F, Wu H, Katritch V, Han G, Jacobson K, Gao Z . Structure of an agonist-bound human A2A adenosine receptor. Science. 2011; 332(6027):322-7. PMC: 3086811. DOI: 10.1126/science.1202793. View

15.

Lyman E, Higgs C, Kim B, Lupyan D, Shelley J, Farid R . A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor. Structure. 2009; 17(12):1660-1668. PMC: 2796422. DOI: 10.1016/j.str.2009.10.010. View

16.

Chini B, Parenti M . G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats. J Mol Endocrinol. 2009; 42(5):371-9. DOI: 10.1677/JME-08-0114. View

17.

Cherezov V, Rosenbaum D, Hanson M, Rasmussen S, Thian F, Kobilka T . High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science. 2007; 318(5854):1258-65. PMC: 2583103. DOI: 10.1126/science.1150577. View

18.

Jo S, Kim T, Iyer V, Im W . CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem. 2008; 29(11):1859-65. DOI: 10.1002/jcc.20945. View

19.

OMalley M, Helgeson M, Wagner N, Robinson A . The morphology and composition of cholesterol-rich micellar nanostructures determine transmembrane protein (GPCR) activity. Biophys J. 2011; 100(2):L11-3. PMC: 3021673. DOI: 10.1016/j.bpj.2010.12.3698. View

20.

Adamian L, Naveed H, Liang J . Lipid-binding surfaces of membrane proteins: evidence from evolutionary and structural analysis. Biochim Biophys Acta. 2010; 1808(4):1092-102. PMC: 3381425. DOI: 10.1016/j.bbamem.2010.12.008. View