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Commenced in January 2007 Frequency: Monthly Edition: International Publications Count: 31200

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Study of Functional Relevant Conformational Mobility of β-2 Adrenoreceptor by Means of Molecular Dynamics Simulation
The study reports about the influence of binding of orthosteric ligands as well as point mutations on the conformational dynamics of β-2-adrenoreceptor. Using molecular dynamics simulation we found that there was a little fraction of active states of the receptor in its apo (ligand free) ensemble corresponded to its constitutive activity. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus receptor’s constitutive activity directly results from its conformational dynamics. On the other hand the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behavior.
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[1] Deupi X., Standfuss J. 2011. Structural Insights into Agonist-Induced Activation of G-Protein-Coupled Receptors. Curr Opin Struct Biol. 21, pp. 541-551.
[2] Costa T., Cotecchia S. 2005. Historical Review: Negative Efficacy and the Constitutive Activity of G-Protein-Coupled Receptors. Trends Pharmacol Sci. 26, pp. 618-624.
[3] Kenakin T. 2002. Efficacy at G-Protein-Coupled Receptors. Nature Reviews Drug Discovery. 1, pp. 103-110.
[4] Canals M., Lane J. R., Wen A., Scammells P. J., Sexton P. M., Christopoulos A. 2012. A Monod-Wyman-Changeux Mechanism Can Explain G Protein-Coupled Receptor (GPCR) Allosteric Modulation. J Biol Chem. 287, pp. 650-659.
[5] Nygaard R., Zou Y., Dror R. O., Mildorf T. J., Arlow D. H., Manglik A., Pan A. C., Liu C. W., Fung J. J., Bokoch M. P. 2013. The Dynamic Process of β-2-Adrenergic Receptor Activation. Cell. 152, pp. 532-542.
[6] Kim T. H., Chung K. Y., Manglik A., Hansen A. L., Dror R. O., Mildorf T. J., Shaw D. E., Kobilka B. K., Prosser R. S. 2013. The Role of Ligands on the Equilibria between Functional States of a G Protein-Coupled Receptor. J Am Chem Soc. pp.
[7] Ma S., Dai Y. 2011. Principal Component Analysis Based Methods in Bioinformatics Studies. Brief Bioinform. pp.
[8] Hayward S., Kitao A., Go N. 1995. Harmonicity and Anharmonicity in Protein Dynamics: A Normal Mode Analysis and Principal Component Analysis. Proteins. 23, pp. 177-186.
[9] Amadei A., Linssen A., De Groot B., Van Aalten D., Berendsen H. 1996. An Efficient Method for Sampling the Essential Subspace of Proteins. Journal of Biomolecular Structure and Dynamics. 13, pp. 615-625.
[10] Novikov G., Sivozhelezov V., Shaitan K. 2013. Study of Structural Dynamics of Ligand-Activated Membrane Receptors by Means of Principal Component Analysis. Biochemistry (Moscow). 78, pp. 403-411.
[11] Javitch J. A., Fu D., Liapakis G., Chen J. 1997. Constitutive Activation of the β2 Adrenergic Receptor Alters the Orientation of Its Sixth Membrane-Spanning Segment. Journal of Biological Chemistry. 272, pp. 18546-18549.
[12] Hilser V. J., Thompson E. B. 2007. Intrinsic Disorder as a Mechanism to Optimize Allosteric Coupling in Proteins. Proceedings of the National Academy of Sciences. 104, pp. 8311-8315.
[13] Unal H., Karnik S. S. 2012. Domain Coupling in GPCRs: The Engine for Induced Conformational Changes. Trends Pharmacol Sci. 33, pp. 79-88.
[14] Scarselli M., Li B., Kim S. K., Wess J. 2007. Multiple Residues in the Second Extracellular Loop are Critical for M3 Muscarinic Acetylcholine Receptor Activation. J Biol Chem. 282, pp. 7385-7396.
[15] Wheatley M., Simms J., Hawtin S., Wesley V., Wootten D., Conner M., Lawson Z., Conner A., Baker A., Cashmore Y. 2007. Extracellular Loops and Ligand Binding to a Subfamily of Family A G-protein-Coupled Receptors. Biochemical Society Transactions. 35, pp. 717.
[16] Bokoch M. P., Zou Y., Rasmussen S. G., Liu C. W., Nygaard R., Rosenbaum D. M., Fung J. J., Choi H. J., Thian F. S., Kobilka T. S., Puglisi J. D., Weis W. I., Pardo L., Prosser R. S., Mueller L., Kobilka B. K. 2010. Ligand-Specific Regulation of the Extracellular Surface of a G-Protein-Coupled Receptor. Nature. 463, pp. 108-112.
[17] Peeters M., Van Westen G., Li Q., Ijzerman A. 2011. Importance of the Extracellular Loops in G Protein-Coupled Receptors for Ligand Recognition and Receptor Activation. Trends Pharmacol Sci. 32, pp. 35-42.
[18] Pauwels P. J., Wurch T. 1998. Review: Amino Acid Domains Involved in Constitutive Activation of G-Protein-Coupled Receptors. Molecular neurobiology. 17, pp. 109-135.
[19] Nygaard R., Frimurer T. M., Holst B., Rosenkilde M. M., Schwartz T. W. 2009. Ligand Binding and Micro-Switches in 7TM Receptor Structures. Trends Pharmacol Sci. 30, pp. 249-259.
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