Hubbard, S. J., Gross, K.-H. & Argos, P. Intramolecular cavities in globular proteins. Protein Eng. Des. Sel. 7, 613–626 (1994).

CAS  Article  Google Scholar 

Williams, M. A., Goodfellow, J. M. & Thornton, J. M. Buried waters and internal cavities in monomeric proteins. Protein Sci. 3, 1224–1235 (1994).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Otting, G., Liepinsh, E. & Wuthrich, K. Protein hydration in aqueous solution. Science 254, 974–980 (1991).

CAS  PubMed  Article  Google Scholar 

Desvaux, H. et al. Dynamics of xenon binding inside the hydrophobic cavity of pseudo-wild-type bacteriophage T4 lysozyme explored through xenon-based NMR spectroscopy. J. Am. Chem. Soc. 127, 11676–11683 (2005).

CAS  PubMed  Article  Google Scholar 

Krimmer, S. G., Cramer, J., Schiebel, J., Heine, A. & Klebe, G. How nothing boosts affinity: hydrophobic ligand binding to the virtually vacated S1′ pocket of thermolysin. J. Am. Chem. Soc. 139, 10419–10431 (2017).

CAS  PubMed  Article  Google Scholar 

Qvist, J., Davidovic, M., Hamelberg, D. & Halle, B. A dry ligand-binding cavity in a solvated protein. Proc. Natl Acad. Sci. USA 105, 6296–6301 (2008).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Otting, G., Liepinsh, E., Halle, B. & Frey, U. NMR identification of hydrophobic cavities with low water occupancies in protein structures using small gas molecules. Nat. Struct. Mol. Biol. 4, 396–404 (1997).

CAS  Article  Google Scholar 

Abiko, L. A., Grahl, A. & Grzesiek, S. High pressure shifts the β1-adrenergic receptor to the active conformation in the absence of G protein. J. Am. Chem. Soc. 141, 16663–16670 (2019).

CAS  PubMed  Article  Google Scholar 

Alexander, S. P. et al. The concise guide to pharmacology 2017/18: G protein-coupled receptors. Br. J. Pharmacol. 174, S17–S129 (2017).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Grahl, A., Abiko, L. A., Isogai, S., Sharpe, T. & Grzesiek, S. A high-resolution description of β1-adrenergic receptor functional dynamics and allosteric coupling from backbone NMR. Nat. Commun. 11, 2216 (2020).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Isogai, S. et al. Backbone NMR reveals allosteric signal transduction networks in the β1-adrenergic receptor. Nature 530, 237–241 (2016).

CAS  PubMed  Article  Google Scholar 

Kofuku, Y. et al. Efficacy of the β2-adrenergic receptor is determined by conformational equilibrium in the transmembrane region. Nat. Commun. 3, 1045 (2012).

PubMed  Article  CAS  Google Scholar 

Latorraca, N. R., Venkatakrishnan, A. J. & Dror, R. O. GPCR dynamics: structures in motion. Chem. Rev. 117, 139–155 (2017).

CAS  PubMed  Article  Google Scholar 

Liu, J. J., Horst, R., Katritch, V., Stevens, R. C. & Wüthrich, K. Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR. Science 335, 1106–1110 (2012).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Manglik, A. & Kobilka, B. The role of protein dynamics in GPCR function: insights from the β2AR and rhodopsin. Curr. Opin. Cell Biol. 27, 136–143 (2014).

CAS  PubMed  Article  Google Scholar 

Okude, J. et al. Identification of a conformational equilibrium that determines the efficacy and functional selectivity of the μ-opioid receptor. Angew. Chem. Int. Ed. 54, 15771–15776 (2015).

CAS  Article  Google Scholar 

Venkatakrishnan, A. J. et al. Molecular signatures of G-protein-coupled receptors. Nature 494, 185–194 (2013).

CAS  PubMed  Article  Google Scholar 

Ye, L., Van Eps, N., Zimmer, M., Ernst, O. P. & Prosser, R.S. Activation of the A2A adenosine G-protein-coupled receptor by conformational selection. Nature 533, 265–268 (2016).

CAS  PubMed  Article  Google Scholar 

Rasmussen, S. G. F. et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 477, 549–555 (2011).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Ballesteros, J. A. & Weinstein, H. in Methods in Neurosciences Vol. 25 (ed. Sealfon, S. C.) 366–428 (Academic Press, 1995).

Trzaskowski, B. et al. Action of molecular switches in GPCRs - theoretical and experimental studies. Curr. Med. Chem. 19, 1090–1109 (2012).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Miller, J. L. & Tate, C. G. Engineering an ultra-thermostable β1-adrenoceptor. J. Mol. Biol. 413, 628–638 (2011).

CAS  PubMed  Article  Google Scholar 

Miller-Gallacher, J. L. et al. The 2.1 Å resolution structure of cyanopindolol-bound β1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor. PLoS One 9, e92727 (2014).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Heydenreich, F. M., Vuckovic, Z., Matkovic, M. & Veprintsev, D. B. Stabilization of G protein-coupled receptors by point mutations. Front. Pharmacol. 6, 82 (2015).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Warne, T. et al. Structure of a β1-adrenergic G-protein-coupled receptor. Nature 454, 486–491 (2008).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Goncalves, J. A. et al. Highly conserved tyrosine stabilizes the active state of rhodopsin. Proc. Natl Acad. Sci. USA 107, 19861–19866 (2010).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Manglik, A. & Kruse, A. C. Structural basis for G protein-coupled receptor activation. Biochemistry 56, 5628–5634 (2017).

CAS  PubMed  Article  Google Scholar 

Oates, J. & Watts, A. Uncovering the intimate relationship between lipids, cholesterol and GPCR activation. Curr. Opin. Struct. Biol. 21, 802–807 (2011).

CAS  PubMed  Article  Google Scholar 

Dawaliby, R. et al. Allosteric regulation of G protein–coupled receptor activity by phospholipids. Nat. Chem. Biol. 12, 35–39 (2016).

CAS  PubMed  Article  Google Scholar 

Salas-Estrada, L. A., Leioatts, N., Romo, T. D. & Grossfield, A. Lipids alter rhodopsin function via ligand-like and solvent-like interactions. Biophys. J. 114, 355–367 (2018).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Song, W., Yen, H.-Y., Robinson, C. V. & Sansom, M. S. P. State-dependent lipid interactions with the A2a receptor revealed by MD simulations using in vivo-mimetic membranes. Structure 27, 392–403.e3 (2019).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Duncan, A. L., Song, W. & Sansom, M. S. P. Lipid-dependent regulation of ion channels and G protein–coupled receptors: insights from structures and simulations. Annu. Rev. Pharmacol. Toxicol. 60, 31–50 (2020).

CAS  PubMed  Article  Google Scholar 

Pucadyil, T. J. & Chattopadhyay, A. Role of cholesterol in the function and organization of G-protein coupled receptors. Prog. Lipid Res. 45, 295–333 (2006).

CAS  PubMed  Article  Google Scholar 

Paila, Y. D. & Chattopadhyay, A. in Cholesterol Binding and Cholesterol Transport Proteins: Structure and Function in Health and Disease (ed. Harris, J. R.) 439–466 (Springer Netherlands, 2010); https://doi.org/10.1007/978-90-481-8622-8_16

Escribá, P. V. et al. Membrane lipid therapy: modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment. Prog. Lipid Res. 59, 38–53 (2015).

PubMed  Article  CAS  Google Scholar 

Gimpl, G. Interaction of G protein coupled receptors and cholesterol. Chem. Phys. Lipids 199, 61–73 (2016).

CAS  PubMed  Article  Google Scholar 

Jafurulla, Md., Aditya Kumar, G., Rao, B. D. & Chattopadhyay, A. A in Cholesterol Modulation of Protein Function: Sterol Specificity and Indirect Mechanisms (eds. Rosenhouse-Dantsker, A. & Bukiya, A. N.) 21–52 (Springer International Publishing, 2019); https://doi.org/10.1007/978-3-030-04278-3_2

Kiriakidi, S. et al. in Direct Mechanisms in Cholesterol Modulation of Protein Function (eds. Rosenhouse-Dantsker, A. & Bukiya, A. N.) 89–103 (Springer International Publishing, 2019); https://doi.org/10.1007/978-3-030-14265-0_5

Casares, D., Escribá, P. V. & Rosselló, C. A. Membrane lipid composition: effect on membrane and organelle structure, function and compartmentalization and therapeutic avenues. Int. J. Mol. Sci. 20, doi:10.3390/ijms20092167, (2019).

Jakubík, J. & El-Fakahany, E. E. Allosteric modulation of GPCRs of class A by cholesterol. Int. J. Mol. Sci. 22, 1953 (2021).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Albert, A. D., Boesze-Battaglia, K., Paw, Z., Watts, A. & Epand, R. M. Effect of cholesterol on rhodopsin stability in disk membranes. Biochim. Biophys. Acta - Protein Struct. Mol. Enzymol. 1297, 77–82 (1996).

Article  Google Scholar 

Gimpl, G. & Fahrenholz, F. Cholesterol as stabilizer of the oxytocin receptor. Biochim. Biophys. Acta - Biomembr. 1564, 384–392 (2002).

CAS  Article