The C9 methyl group of retinal interacts with glycine-121 in rhodopsin

Han, May; Groesbeek, M.; Sakmar, Thomas P.; Smith, Steven O.

doi:10.1073/pnas.94.25.13442

Cited by 71 publications

(73 citation statements)

References 43 publications

(62 reference statements)

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“…Thus, structural changes in the region near Glu 122 and His 211 are required for proper repositioning of the ␤-ionone ring (27). Previous studies have show a direct interaction between 11-cis-retinal and Gly 121 in rhodopsin TM III (31)(32)(33)(34)(35). The increase in the size of Gly 121 correlated directly with the increasing dark state activity.…”

Section: Discussionmentioning

confidence: 86%

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Stojanović

Stitham

Hwa

2004

Journal of Biological Chemistry

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Zinc deficiency and retinitis pigmentosa are both important factors resulting in retinal dysfunction and night blindness. In this study, we address the critical biochemical and structural relevance of zinc ions in rhodopsin and examine whether zinc deficiency can lead to rhodopsin dysfunction. We report the identification of a high-affinity zinc coordination site within the transmembrane domain of rhodopsin, coordinated by the side chains of two highly conserved residues, Glu 122 in transmembrane helix III and His 211 in transmembrane helix V. We also demonstrate that this zinc coordination is critical for rhodopsin folding, 11-cis-retinal binding, and the stability of the chromophore-receptor interaction, defects of which are observed in retinitis pigmentosa. Furthermore, a cluster of retinitis pigmentosa mutations is localized within and around this zinc binding site. Based on these studies, we believe that improvement in zinc binding to rhodopsin at this site within the transmembrane domain may be a pharmacological approach for the treatment of select retinitis pigmentosa mutations. Transmembrane coordination of zinc may also be an important common principle across G-protein-coupled receptors.Several neurodegenerative disorders, Alzheimer disease, Parkinson disease, familial amyotrophic lateral sclerosis, and the transmissible spongiform encephalopathies, share a common pathogenesis involving the misfolding and aggregation of specific proteins. Mounting evidence has demonstrated the direct binding of zinc (Zn 2ϩ ) to the ␤-amyloid (Alzheimer disease), ␣-synuclein (Parkinson disease), superoxide dismutase (amyotrophic lateral sclerosis), and prion (transmissible spongiform encephalopathies) proteins, linking either the gain or loss of Zn 2ϩ binding to the progression of these severe protein misfolding disorders. Zn 2ϩ promotes aggregation of the highly fibrillogenic prion peptide, PrP106 -126 (1), and of the ␤-amyloid protein (2-4) into amyloidogenic aggregates. Clioquinol, a metal chelating agent, is currently being investigated as a potential therapeutic solution to inhibit ␤-amyloid neurotoxicity (5). In contrast, in mutant superoxide dismutase protein, loss of affinity for Zn 2ϩ results in diminished protein activity (6), reduced protein stability (7), and formation of amyloid-like filaments (8). Thus, both zinc deficiencies and excesses can lead to neurodegenerative diseases.In the G protein-coupled photoreceptor rhodopsin, there have been over 100 distinct, heritable mutations identified, many of which induce an altered protein conformation, misfolding, aggregation, and cell death, followed by the clinical manifestation of the retinal neurodegenerative disorder retinitis pigmentosa (9). Interestingly, Zn 2ϩ deficiency is also known to cause retinal neurodegeneration and night blindness (10), symptoms reminiscent of retinitis pigmentosa. Furthermore, Zn 2ϩ has been shown to directly bind rhodopsin (11,12) and to reduce rhodopsin thermal stability and regeneration with 11-cis-retinal at higher Zn 2ϩ concen...

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Section: Discussionmentioning

confidence: 86%

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Stojanović

Stitham

Hwa

2004

Journal of Biological Chemistry

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“…In particular, the results strongly underlie the importance of the protein cavity in forming a part of the solvation environment dictating the type of conformational change that will be determined by the light-activated retinal. 15,[100][101][102][103][104][105][106][107][108] In that sense, the nature of these sidechain and main chain interactions drive a preference for a particular type of excited state and a particular type of relaxation response. Experimental work that shifts the nature of retinal further supports this type of thinking.…”

Section: Implications For Spectral Tuningmentioning

confidence: 99%

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Stevens

Woolf

2006

Proteins

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Rhodopsin is the prototypical G-protein coupled receptor, coupling light activation with high efficiency to signaling molecules. The dark-state X-ray structures of the protein provide a starting point for consideration of the relaxation from initial light activation to conformational changes that may lead to signaling. In this study we create an energetically unstable retinal in the light activated state and then use molecular dynamics simulations to examine the types of compensation, relaxation, and conformational changes that occur following the cis-trans light activation. The results suggest that changes occur throughout the protein, with changes in the orientation of Helices 5 and 6, a closer interaction between Ala 169 on Helix 4 and retinal, and a shift in the Schiff base counterion that also reflects changes in sidechain interactions with the retinal. Taken together, the simulation is suggestive of the types of changes that lead from local conformational change to light-activated signaling in this prototypical system.

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“…Most of the altered ligands are less effective agonists in the all-trans state, shifting the MI-MII equilibrium back toward MI [25][26][27] . The C9 methyl group distal to the retinylidene Schiff base of Lys 296 is known to play an essential role 25,27,28 . Moreover, the β-ionone ring of retinal is crucially important for rhodopsin activation 26,29,30 .…”

Section: Introductionmentioning

confidence: 99%

Dynamic Structure of Retinylidene Ligand of Rhodopsin Probed by Molecular Simulations

Lau

Grossfield

Feller

et al. 2007

Journal of Molecular Biology

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SummaryRhodopsin is currently the only available atomic-resolution template for understanding biological functions of the G protein-coupled receptor (GPCR) family. The structural basis for the phenomenal dark state stability of 11-cis-retinal bound to rhodopsin and its ultrafast photoreaction are active topics of research. In particular, the β-ionone ring of the retinylidene inverse agonist is crucial for the activation mechanism. We analyzed a total of 23 independent, 100-ns all-atom molecular dynamics simulations for rhodopsin embedded in a lipid bilayer in the microcanonical (N,V,E) ensemble. Analysis of intramolecular fluctuations predicts hydrogen-out-of-plane (HOOP) wagging modes of retinal consistent with those found in Raman vibrational spectroscopy. We show that sampling and ergodicity of the ensemble of simulations are crucial for determining the distribution of conformers of retinal bound to rhodopsin. The polyene chain is rigidly locked into a single, twisted conformation, consistent with the function of retinal as an inverse agonist in the dark state. Most surprisingly, the β-ionone ring is mobile within its binding pocket; interactions are nonspecific and the cavity is sufficiently large to enable structural heterogeneity. We find that retinal occupies two distinct conformations in the dark state, contrary to most previous assumptions. The β-ionone ring can rotate relative to the polyene chain, thereby populating both positively and negatively twisted 6-s-cis enantiomers. This result, while unexpected, strongly agrees with experimental solid-state 2 H NMR spectra. Correlation analysis identifies the residues most critical to controlling mobility of retinal; we find that Trp 265 moves away from the ionone ring prior to any conformational transition. Our findings reinforce how Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Graphical AbstractCover. Structure of retinal ligand of G protein-coupled receptor rhodopsin in the inverse agonist form as obtained from molecular simulations.

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The C9 methyl group of retinal interacts with glycine-121 in rhodopsin

Cited by 71 publications

References 43 publications

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

Critical Role of Transmembrane Segment Zinc Binding in the Structure and Function of Rhodopsin

How a small change in retinal leads to G‐protein activation: Initial events suggested by molecular dynamics calculations

Dynamic Structure of Retinylidene Ligand of Rhodopsin Probed by Molecular Simulations

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