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2001 | 48 | 1 | 83-93
Article title

Molecular modelling study of the role of cholesterol in the stimulation of the oxytocin receptor.

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Cholesterol, an integral component of membranes in Eucaryota, is a modifier of membrane properties. In vivo studies have demonstrated that cholesterol can also modulate activities of some G protein-coupled receptors (GPCRs), which are integral membrane proteins. This can result either from an effect of cholesterol on the membrane fluidity or from specific interactions of the membrane cholesterol with the receptor, as recently demonstrated for the cholecystokinin type β (CCKRβ) or the oxytocin receptor (OTR). Using molecular modelling, we studied conformational preferences of cholesterol and several of its analogues. Subsequently, we simulated the distributions of their preferred conformations around the surface of OTR, CCKRβ and a chimeric oxytocin/cholecystokinin receptor. Consequently, we suggest residues on the surface of OTR which are potentially significant in the OTR/cholesterol interaction.
Physical description
  • Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
  • Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
  • Institute of Biochemistry, Johannes-Gutenberg-University, Mainz, Germany
  • Institute of Biochemistry, Johannes-Gutenberg-University, Mainz, Germany
  • Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
  • Albert, A.D., Young, J.E. & Yeagle, P.L. (1996) Rhodopsin-cholesterol interactions in bovine rod outer segment disk membranes. Biochim. Biophys. Acta. 1285, 47-55.
  • Baldwin, J.M. (1993) The probable arrangement of the helices in G-protein-coupled receptors. EMBO J. 12, 1693-1703.
  • Baldwin, J.M., Scheltler, G.F.X. & Unger, V.M. (1997) An alpha-carbon template for the transmembrane helices in the rhodopsin family of G-protein-coupled receptors. J. Mol. Biol. 272, 144-164.
  • Bloch, K.E. (1983) Sterol structure and membrane function. CRC Crit. Rev. Biochem. 14, 47-82.
  • Boesze-Battaglia, K. & Albert, A.D. (1990). Cholesterol modulation of photoreceptor function in bovine retinal rod outer segments. J. Biol. Chem. 265, 20727-20730.
  • Brzustowicz, M.R. (1999) Molecular organization of cholesterol in polyunsaturated phospholipid membranes: A solid state 2H NMR investigation. FEBS Lett. 451, 197-202.
  • Carruthers, A. & Melchior, D.L. (1993) Studies of the relationship between bilayer water permeability and physical state. Biochemistry 22, 5797-5807.
  • Corpet, F. (1988) Multiple sequence alignment with hierarhical clustering. Nucleic Acids Res. 16, 10881- 10890.
  • Case, D.A., Pearlman, D.A., Caldwell, J.W., Cheatham III, T.E., Ross, W.S., Simmerling, C., Darden, T., Merz., K.M., Stanton, R.V., Cheng, A., Vincent, J.J., Crowley, M., Ferguson, D.M., Radmer, R., Seibel, G.L., Singh, U.C., Weiner, P.K. & Kollman, P.A. (1997) AMBER, v.5.0. University of California, San Francisco, CA, U.S.A.
  • Gieldoń, A., Kaźmierkiewicz, R., Ślusarz, R. & Ciarkowski, J. (2000) Affinities of YM087, a non-peptide vasopressin V1a and V2 receptor antagonist, toward its biological targets. J. Comp.-Aided Molec. Design. (Submitted).
  • Gimpl, G., Burger, K. & Fahrenholz, F. (1997) Cholesterol as modulator of receptor function. Biochemistry 36, 10959-10974.
  • Gimpl, G., Klein, U., Reiländer, H. & Fahrenholz, F. (1995) Expression of the human oxytocin receptor in baculovirus-infected insect cells: High-affinity binding is induced by a cholesterol-cyclodextrin complex. Biochemistry 34, 13794-13801.
  • Herzyk, P. & Hubbard, R.E. (1995) Automated method for modeling seven-helix transmembrane receptors from experimental data. Biophys. J. 69, 2419- 2442.
  • Klein, U., Gimpl, G. & Fahrenholz, F. (1995) Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34, 13784-13793.
  • Koradi, R., Billeter, M. & Wüthrich, K. (1996) MOLMOL, a program for display and analysis of macromolecular structures. J. Mol. Graphics 14, 51-55.
  • Liscum, L. & Underwood, K.W. (1995) Intracellular cholesterol transport and compartmentation. J. Biol. Chem. 270, 15443-5446.
  • Maneri, L.R. & Low, P.S. (1988) Structural stability of the erythrocyte anion transporter, band 3, in different lipid environments. A differential scanning calorimetric study. J. Biol. Chem. 263, 16170-16178.
  • Méléard, P., Gerbeaud, C., Pott, T., Fernandez-Puente, L., Bivas, I., Mitov, M.D., Dufourcq, J. & Bothorel, P. (1997) Bending elasticities of model membranes: Influences of temperature and sterol content. Biophys. J. 72, 2616-2629.
  • Morris, G.M., Goodsell, D.S., Huey, R. & Olson, A.J. (1996) Distributed automated docking of flexible ligands to proteins: Parallel applications of AutoDock 2.4. J. Comp.-Aided Molec. Design. 10, 293-304.
  • Narayanaswami, V. & McNamee, M.G. (1993) Protein-lipid interactions and Torpedo californica nicotinic acetylcholine receptor function. 2. Membrane fluidity and ligand-mediated alteration in the accessibility of gamma subunit cysteine residues to cholesterol. Biochemistry 32, 12420-12427.
  • Nunez, M.T. & Glass, J. (1982) Reconstitution of the transferrin receptor in lipid vesicles. Effect of cholesterol on the binding of transferrin. Biochemistry 21, 4139-4143.
  • Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Le Trong, I., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M. & Miyano, M. (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289, 739- 745.
  • Pang, L., Graziano, M. & Wang, S. (1999) Membrane cholesterol modulates galanin-GalR2 interaction. Biochemistry 38, 12003-12011.
  • PCModel (1991) Serena Software, Box 3076, Bloomington, IN 47402-3076, U.S.A.
  • Peitsch, M.C., Herzyk, P., Wells, T.N.C. & Hubbard, R.E. (1995) Automated G protein-coupled receptor modelling of Swiss-model. swissmod/SWISS-MODEL.htlm.
  • Pogozheva, I.D., Lomize, A.L. & Mosberg, H.I. (1998) Opioid receptor three-dimensional structures from distance geometry calculations with hydrogen bonding constraints. Biophys. J. 75, 612-634.
  • Rohrer, D.C., Duax, W.L., Griffin, J.F. & Weeks, C.M. (1980) Conformational analysis of sterols: Comparison of X-ray crystallographic observations with data from other sources. Lipids 15, 783-792.
  • Schertler, G.F.X. & Hargrave, P.A. (1995) Projection structure of frog rhodopsin in two crystal forms. Proc. Natl. Acad. Sci. U.S.A. 92, 11578-11582.
  • Schroeder, F., Jefferson, J.R., Kier, A.B., Knittel, J., Scallen, T.J., Wood, W.G. & Hapala, I. (1991) Membrane cholesterol dynamics: Cholesterol domains and kinetic pools. Proc. Soc. Exp. Biol. Med. 196, 235-252.
  • Shieh, H.-S., Hoard, L.G. & Nordman, C.E. (1981) The structure of cholesterol. Acta Cryst. B37, 1538- 1543.
  • Sprang, S.R. (1997) G protein mechanisms. Insights from structural analysis. Annu. Rev. Biochem. 66, 639-678.
  • Stryer, L. (1995) Biochemistry. Fourth edn., W.H. Freeman & Company, New York.
  • SYBYL 6.6 (1999) Tripos Inc. 1699 South Hanley Rd., St. Louis, MO 63144, U.S.A.
  • Tu, K., Klein, M.L. & Tobias, D.J. (1998) Constant-pressure molecular dynamics investigation of cholesterol effects in a dipalmitoylphosphatidylcholine bilayer. Biophys. J. 75, 2147-2156.
  • Unger, V.M., Hargrave, P.A., Baldwin, J.M. & Schertler, G.F.X. (1997) Arrangement of rhodopsin transmembrane alpha-helices. Nature 389, 203-206.
  • Xiang, T.X. & Anderson, B.D. (1997) Permeability of acetic acid across gel and liquid-crystalline lipid bilayers conforms to free-surface-area theory. Biophys. J. 72, 223-237.
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