2021  1,540
2020  1,374
2019  1,023
2018  0,932
2017  0,977
2016  0,799
2015  0,662
2014  0,740
2013  0,739
2012  0,637
2011  0,658
2010  0,654
2009  0,570
2008  0,849
2007  0,805
2006  0,330
2005  0,435
2004  0,623
2003  0,567
2002  0,641
2001  0,490
2000  0,477
1999  0,762
1998  0,785
1997  0,507
1996  0,518
1995  0,502
Vol 48(2014) N 3 p. 399-413; DOI 10.1134/S0026893314030157 Full Text

G.V. Novikov1*, V.S. Sivozhelezov1, K.V. Shaitan2

Influence of Orthosteric Ligand Binding on the Conformational Dynamics of the β-2-Adrenergic Receptor via Essential Dynamics Sampling Simulation

1Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, 142290, Russia
2Department of Biology, Moscow State University, Moscow, 119991, Russia

Received - 2013-08-12; Accepted - 2013-11-19

The influence of the binding of orthosteric ligands on the conformational dynamics of the β-2- adrenoreceptor was identified using the molecular dynamics method. It was found that there was a small fraction of active states of the receptor in its apo (ligand free) ensemble. An analysis of the MD trajectories indicated that this spontaneous activation of the receptor was accompanied by the motion of its VI helix. Thus, the receptor's constitutive activity is a direct result of its conformational dynamics. On the other hand, the binding of the full agonist resulted in a significant shift in the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized receptor in its inactive state. It is likely that the binding of the inverse agonists might be a universal method of the constitutive activity inhibition. Our results indicate that ligand binding redistributes preexisting conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux Model), rather than causes an induced fit. Therefore, the ensemble of the biologically relevant receptors conformations has been encoded in its spatial structure and individual conformations from that ensemble and might be used by the cell according to the physiological behavior.

seven-transmembrane receptors, conformational dynamics, receptor activation, X-ray crystallography, principal-components analysis, molecular dynamics, constitutive activity