Molecular Dynamics Simulations of the Ligand‐Induced Chemical Information Transfer in the 5‐HT<sub>1A</sub> Receptor.

Seeber, Michele; Benedetti, Pier G. De; Fanelli, Francesca

doi:10.1002/chin.200350240

Cited by 9 publications

(20 citation statements)

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“…According to extensive computational analyses, hallmarks of the ligand-induced active and non-active forms of the receptors were found to involve R3.50, the arginine of the E/DRY motif, and the cytosolic extensions of H3 and H6. In fact, for the agonistbound (i.e., active) and the antagonist-bound (i.e., nonactive) forms, the establishment of crucial intermolecular interactions (as suggested by experimental evidences) was found, respectively, concurrent with destabilization and reinforcement of the intramolecular interactions that involve the E/DRY arginine in the empty receptor forms [42,44,45]. For the MCHRs and the TXA 2 R, other structural changes in the cytosolic domains peculiar to the agonist-bound forms include the opening of a solvent accessible crevice involving I2 and the cytosolic extensions of H3 and H6 [45,46].…”

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 88%

“…The receptor sites in which most of such similarities occur essentially concern selected positions in the extracellular halves of H3, H5 and H6. Computational modeling of the agonist-bound forms of the 5-HT 1A , MCH, OT and TXA 2 receptors suggests that these receptor portions hold the key contact points for the ligand moieties responsible for efficacy [42,[44][45][46]. According to extensive computational analyses, hallmarks of the ligand-induced active and non-active forms of the receptors were found to involve R3.50, the arginine of the E/DRY motif, and the cytosolic extensions of H3 and H6.…”

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 97%

“…These configurations differ from those of the empty receptor forms. On the other hand, comparing a large number of average configurations obtained for the different agonistand antagonist-receptor complexes following different computational protocols, it was possible to infer similarities in the interaction modes of the different agonists at their cognate receptors [42,[44][45][46]. The receptor sites in which most of such similarities occur essentially concern selected positions in the extracellular halves of H3, H5 and H6.…”

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 99%

“…For both the 5-HT 1A receptor and the two MCHR subtypes, these interactions include an intermolecular salt bridge that allows the crucial aromatic moiety of the agonist to establish the proper interaction with one member of the aromatic cluster in H6 [42,45]. In line with these observations, also for the OT-OTR complexes, the few critical intermolecular interactions essential for the structural information transfer include that between Tyr2 of the agonist and F291(6.51) of the aromatic cluster in H6 [44].…”

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 99%

“…[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%

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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: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 88%

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 97%

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 99%

Section: Intramolecular Communication Betw-een Distal Receptor Sites:mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Fanelli¹,

Benedetti²,

Raimondi³

et al. 2009

CPPS

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Structural features of the inactive and active states of the melanin‐concentrating hormone receptors: Insights from molecular simulations

Vitale¹,

Pedone²,

Benedetti³

et al. 2004

Proteins

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Comparative molecular dynamics simulations of both subtypes 1 and 2 of the melanin-concentrating hormone receptor (MCHR1 and MCHR2, respectively) in their free and hormone-bound forms have been carried out. The hormone has been used in its full-length and truncated forms, as well as in 16 mutated forms. Moreover, MCHR1 has been simulated in complex with T-226296, a novel orally active and selective antagonist. The comparative analysis of an extended number of receptor configurations suggests that the differences between inactive (i.e., free and antagonist-bound) and active (i.e., agonist-bound) states of MCHRs involve the receptor portions close to the E/DRY and NPxxY motifs, with prominence to the cytosolic extensions of helices 2, 3, 6, and 7. In fact, the active forms of these receptors share the release of selected intramolecular interactions found in the inactive forms, such as that between R3.50 of the E/DRY motif and D2.40, and that between Y7.53 of the NPxxY motif and F7.60. Another feature of the active forms of both MCHRs is the approach of "helix 8" to the cytosolic extension of helix 3. These features of the active forms are concurrent with the opening of a cleft at the cytosolic end of the helix bundle. For both MCHRs, the agonist-induced chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor.

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Modeling G protein‐coupled receptors for structure‐based drug discovery using low‐frequency normal modes for refinement of homology models: Application to H3 antagonists

et al. 2009

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G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low-frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions.

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Molecular Dynamics Simulations of the Ligand‐Induced Chemical Information Transfer in the 5‐HT_1A Receptor.

Cited by 9 publications

References 1 publication

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Structural features of the inactive and active states of the melanin‐concentrating hormone receptors: Insights from molecular simulations

Modeling G protein‐coupled receptors for structure‐based drug discovery using low‐frequency normal modes for refinement of homology models: Application to H3 antagonists

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Molecular Dynamics Simulations of the Ligand‐Induced Chemical Information Transfer in the 5‐HT1A Receptor.

Cited by 9 publications

References 1 publication

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Computational Modeling of Intramolecular and Intermolecular Communication in GPCRs

Structural features of the inactive and active states of the melanin‐concentrating hormone receptors: Insights from molecular simulations

Modeling G protein‐coupled receptors for structure‐based drug discovery using low‐frequency normal modes for refinement of homology models: Application to H3 antagonists

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Molecular Dynamics Simulations of the Ligand‐Induced Chemical Information Transfer in the 5‐HT_1A Receptor.