Light Activation of Rhodopsin: Insights from Molecular Dynamics Simulations Guided by Solid-State NMR Distance Restraints

Department of Biological Sciences, University of Essex, Wivenhoe Park, Essex C04 3SQ, UK
Journal of Molecular Biology (Impact Factor: 4.33). 02/2010; 396(3):510-527. DOI: 10.1016/j.jmb.2009.12.003

ABSTRACT Structural restraints provided by solid-state NMR measurements of the metarhodopsin II intermediate are combined with molecular dynamics simulations to help visualize structural changes in the light activation of rhodopsin. Since the timescale for the formation of the metarhodopsin II intermediate (> 1 ms) is beyond that readily accessible by molecular dynamics, we use NMR distance restraints derived from 13C dipolar recoupling measurements to guide the simulations. The simulations yield a working model for how photoisomerization of the 11-cis retinylidene chromophore bound within the interior of rhodopsin is coupled to transmembrane helix motion and receptor activation. The mechanism of activation that emerges is that multiple switches on the extracellular (or intradiscal) side of rhodopsin trigger structural changes that converge to disrupt the ionic lock between helices H3 and H6 on the intracellular side of the receptor.

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    • "er isolation of various photointermediate states of rhodopsin that dis - play characteristic absorbance maxima ( Matthews et al . , 1963 ; Yoshizawa and Wald , 1964 ; Thorgeirsson et al . , 1993 ) More recent EPR studies have revised these initial estimates for conformational alterations to ϳ6 - to 10 - Å displacements ( Altenbach et al . , 2008 ; Hornak et al . , 2010 ) . Furthermore , the chemical differences between the Meta I and Meta II states simply involve the changes in protonation state , and each of these states is in equi - librium . Were large scale movements of entire helices before G protein binding involved , it is thermodynami - cally unlikely that the equilibrium between the states co"
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    • "The thermodynamic stabilities of these states are not known quantitatively and will vary with receptor and ligand, although it is clear that the agonist state is very unstable (Gether et al., 1997). Intermediate and transition states between these major conformations must also exist on the activation pathway(s), which is gradually becoming clearer from a combination of structural, spectroscopic and mutational studies (Hornak et al., 2010; Tate and Schertler, 2009). Thus we are confronted with a complex conformational landscape but one which is dominated by major receptor states, which when trapped by ligands or mutations will correspond to key pharmacological phenotypes (Colquhoun, 1998). "
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