Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors?

Archer, Elodie; Maigret, Bernard; Escrieut, Chantal; Pradayrol, Lucien; Fourmy, Daniel

doi:10.1016/s0165-6147(02)00009-3

Cited by 107 publications

(98 citation statements)

References 39 publications

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“…The negative allosteric modulators NPS 2143 and Calhex 231 can either block direct contact of the Venus flytrap module with the seven TM region of the receptor that functions as a dimer, or can prevent the switch between the inactive and active conformation of the TM region, thus preventing further rotation of TM6 required for activation of many GPCRs (32). No attempt was made to model the CaSR in its activated form bound to Calindol or NPS R-568, because of the lack of an adequate three-dimensional template (33). However, our data emphasizes the crucial role of Glu-837 in anchoring NPS R-568, as previously observed (17,19), and of Calindol, presumably through a salt bridge with the protonated secondary amine of the two compounds as we previously proposed for the calcilytics.…”

Section: Discussionsupporting

confidence: 44%

Positive and Negative Allosteric Modulators of the Ca2+-sensing Receptor Interact within Overlapping but Not Identical Binding Sites in the Transmembrane Domain

Pétrel

Kessler

Dauban

et al. 2004

Journal of Biological Chemistry

195

167

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A three-dimensional model of the human extracellular Ca 2؉ -sensing receptor (CaSR) has been used to identify specific residues implicated in the recognition of two negative allosteric located in transmembranes (TM) 6 and TM7, in the binding pocket for both calcimimetics and calcilytics, despite important differences observed between each family of compounds. The TMs involved in the recognition of both calcilytics include residues located in TM3 (Arg-680 3.28 , Phe-684 3.32 , and Phe-688 3.36 ). However, our study indicates subtle differences between the binding of these two compounds. Importantly, the observation that some mutations that have no effect on calcimimetics recognition but which affect the binding of calcilytics in TM3 and TM5, suggests that the binding pocket of positive and negative allosteric modulators is partially overlapping but not identical. Our CaSR model should facilitate the development of novel drugs of this important therapeutic target and the identification of the molecular determinants involved in the binding of allosteric modulators of class 3 G-protein-coupled receptors.

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Section: Discussionsupporting

confidence: 44%

Positive and Negative Allosteric Modulators of the Ca2+-sensing Receptor Interact within Overlapping but Not Identical Binding Sites in the Transmembrane Domain

Pétrel

Kessler

Dauban

et al. 2004

Journal of Biological Chemistry

195

167

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“…3,[128][129][130] This is especially important due to the large number of important pharmacological targets within the large GPCR family. [131][132][133][134][135][136][137][138][139][140][141][142] In our simulation results, the nature of the coupling between a local conformational change and a large-scale helix and loop change may be similar across the GPCR family.…”

Section: Implications For Other Gpcr Systemsmentioning

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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“…An early discrimination of the investigated ligands into these categories in silico is of high importance for pharmaceutical research. Most GPCR crystal structures represent an inactive state which has been considered to be capable for the discovery of antagonists and inverse agonists only [12][13][14]. To date, only the structure of opsin [15] and most recently structural models of active conformations of the b 2 -adrenergic receptor (B2AR) [16][17][18], the agonist-bound b 1 -adrenergic receptor [19] and a constitutively active rhodopsin [20] could be potentially used as a template for the modelling of active GPCRs and subsequent virtual screening for agonists.…”

Section: Introductionmentioning

confidence: 99%

The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays

et al. 2011

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a b s t r a c tMost of the currently available G protein-coupled receptor (GPCR) crystal structures represent an inactive receptor state, which has been considered to be suitable only for the discovery of antagonists and inverse agonists in structure-based computational ligand screening. Using the b 2 -adrenergic receptor (B2AR) as a model system, we show that a dynamic homology model based on an ''active'' opsin structure without further incorporation of experimental data performs better than the crystal structure of the inactive B2AR in finding agonists over antagonists/inverse agonists. Such ''active-like state'' dynamic homology models can therefore be used to selectively identify GPCR agonists in in silico ligand libraries.

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Rhodopsin crystal: new template yielding realistic models of G-protein-coupled receptors?

Cited by 107 publications

References 39 publications

Positive and Negative Allosteric Modulators of the Ca2+-sensing Receptor Interact within Overlapping but Not Identical Binding Sites in the Transmembrane Domain

Positive and Negative Allosteric Modulators of the Ca2+-sensing Receptor Interact within Overlapping but Not Identical Binding Sites in the Transmembrane Domain

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

The structure of active opsin as a basis for identification of GPCR agonists by dynamic homology modelling and virtual screening assays

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