Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling

Fanelli, Francesca; Benedetti, Pier G. De

doi:10.1007/s10822-006-9064-0

Cited by 32 publications

(31 citation statements)

References 99 publications

(183 reference statements)

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“…[1]), members of the glycoprotein receptor subfamily [33][34][35][36][37][38][39] (reviewed also in Refs. [1,40,41]), as well as the receptors for serotonin [42], oxytocin (OT) [43,44], melanine- Fig. (1).…”

Section: Introductionmentioning

confidence: 99%

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Fanelli¹,

Benedetti²,

Raimondi³

et al. 2009

CPPS

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Intramolecular and intermolecular communication is a privileged issue in G protein-Coupled Receptor (GPCR) function as the prominent role of these receptors is to respond to extracellular signals by catalyzing nucleotide exchange in intracellular G proteins. In the last decade or so we have applied much effort in elaborating computational strategies to infer the mechanisms of intramolecular and intermolecular communication in a number of GPCRs of the rhodopsin family. In this article, we review the most relevant achievements on the matter. In summary, the receptor sites of activating mutations or ligand-binding communicate with a common allosteric site in the cytosolic domains. This was inferred from the observation that local perturbations by activating mutations or ligands correlate with increases in solvent accessibility of the neighborhoods of the highly conserved E/DRY receptor motif. The latter turned out to be the primary recognition point for the C-terminus of the G protein alpha-subunit, independent of the receptor or the G protein type. In spite of the highly composite nature of the receptor-G protein interface, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed formation of a nucleotide exit route. The latter would lie in between the alphaF-helix and the beta6/alpha5 loop, which detach from each other upon receptor binding, giving solvent accessibility to the nucleotide. A worthy inference of the studies is that GPCRs employ common pathways for the transfer of functionally relevant information.

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Section: Introductionmentioning

confidence: 99%

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Fanelli¹,

Benedetti²,

Raimondi³

et al. 2009

CPPS

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“…In this new version we added the possibility to give the destination coordinates of the receptor as additional input information into the algorithm. During the activation process of a GPCR long range movements of TM VI are described in literature [25][26][27][28][29][30][31][32], which we could not observe entirely in the old version. Therefore we allow the receptor atoms to be translated from their actual position into their destination position on an analogous guiding line as described for the ligand in [35].…”

Section: Modeling Of the Inactive And Active Receptormentioning

confidence: 80%

“…Niv et al [24] gave a very good summary about the structural properties of inactive and active bovine rhodopsin and other GPCRs. During the activation process the intracellular part of transmembrane helix (TM) VI moves away from the intracellular part of TM III, that means, the ionic lock between Arg 3.50 and Gln 6.30 is destroyed [25][26][27][28][29][30][31][32]. This movement results in a straightening of TM VI.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor

Straßer

Wittmann

2007

J Comput Aided Mol Des

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The Histamine H(1)-receptor (H1R), belonging to the amine receptor-class of family A of the G-protein coupled receptors (GPCRs) gets activated by agonists. The consequence is a conformational change of the receptor, which may involve the binding-pocket. So, for a good prediction of the binding-mode of an agonist, it is necessary to have knowledge about these conformational changes. Meanwhile some experimental data about the structural changes of GPCRs during activation exist. Based on homology modeling of the guinea-pig H1R (gpH1R), using the crystal structure of bovine rhodopsin as template, we performed several MD simulations with distance restraints in order to get an inactive and an active structure of the gpH1R. The calculations led to a Phe6.44/Trp6.48/Phe6.52-switch and linearization of the proline kinked transmembrane helix VI during receptor activation. Our calculations showed that the Trp6.48/Phe6.52-switch induces a conformational change in Phe6.44, which slides between transmembrane helices III and VI. Additionally we observed a hydrogen bond interaction of Ser3.39 with Asn7.45 in the inactive gpH1R, but because of a counterclockwise rotation of transmembrane helix III Ser3.39 establishes a water-mediated hydrogen bond to Asp2.50 in the active gpH1R. Additionally we simulated a possible mechanism for receptor activation with a modified LigPath-algorithm.

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“…Comparison of the resulting different models with site-directed spinlabel experimental data allowed to identify the most plausible conformation of the TM bundle, which was completed with loops, N-and C-terminal fragments. A comparative analysis of molecular dynamics studies of several normal and/or mutated GPCR subtypes in their free and/ or ligand-bound forms was also used by Fanelli and coworkers to infer about structural features that are unique to specific conformational states [60]. Specifically, weakening of the salt-bridge formed by the highly conserved arginine of the E/DRY motif, and the increase in solvent accessibility of the cytosolic interface between helices 3 and 6 were found to be largely responsible for the difference between inactive and active states of GPCRs.…”

Section: Activated Modelsmentioning

confidence: 99%

Advances in the development and application of computational methodologies for structural modeling of G-protein-coupled receptors

Mobarec¹,

Filizola²

2008

Expert Opinion on Drug Discovery

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Background-Despite the large amount of experimental data accumulated in the past decade on G-protein coupled receptor (GPCR) structure and function, understanding of the molecular mechanisms underlying GPCR signaling is still far from being complete, thus impairing the design of effective and selective pharmaceuticals.Objective-Understanding of GPCR function has been challenged even further by more recent experimental evidence that several of these receptors are organized in the cell membrane as homoor hetero-oligomers, and that they may exhibit unique pharmacological properties. Given the complexity of these new signaling systems, researcher's efforts are turning increasingly to molecular modeling, bioinformatics and computational simulations for mechanistic insights of GPCR functional plasticity.Methods-We review here current advances in the development and application of computational approaches to improve prediction of GPCR structure and dynamics, thus enhancing current understanding of GPCR signaling.Results/Conclusions-Models resulting from use of these computational approaches further supported by experiments are expected to help elucidate the complex allosterism that propagates through GPCR complexes, ultimately aiming at successful structure-based rational drug design.

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Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling

Cited by 32 publications

References 99 publications

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor

Advances in the development and application of computational methodologies for structural modeling of G-protein-coupled receptors

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