Prediction of the 3D Structure of FMRF‐amide Neuropeptides Bound to the Mouse MrgC11 GPCR and Experimental Validation

Heo, Jiyoung; Han, Sang‐Kyou; Vaidehi, Nagarajan; Wendel, John; Kekenes‐Huskey, Peter M.; Goddard, William A.

doi:10.1002/cbic.200700188

Cited by 24 publications

(28 citation statements)

References 34 publications

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“…As observed above for MrgA1, when transfected in astrocytes, activation of MrgC11 by application of the FMRFa agonist triggered calcium transients. Interestingly, MrgC11 has known silent mutants (MrgC11Y110A [MrgC11-Tyr] [37] and MrgC11D179A [MrgC11-Asp] [37]) that could be used as negative controls. Indeed, astrocytes infected with the silent mutants of MrgC11 were unable to generate Ca 2+ spikes in response to FMRFa ( Figure 4A).…”

Section: Activation Of Paps At Single Synapses Increases Spine Coveramentioning

confidence: 99%

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

et al. 2014

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SummaryBackground: Excitatory synapses in the CNS are highly dynamic structures that can show activity-dependent remodeling and stabilization in response to learning and memory. Synapses are enveloped with intricate processes of astrocytes known as perisynaptic astrocytic processes (PAPs). PAPs are motile structures displaying rapid actin-dependent movements and are characterized by Ca 2+ elevations in response to neuronal activity. Despite a debated implication in synaptic plasticity, the role of both Ca 2+ events in astrocytes and PAP morphological dynamics remain unclear. Results: In the hippocampus, we found that PAPs show extensive structural plasticity that is regulated by synaptic activity through astrocytic metabotropic glutamate receptors and intracellular calcium signaling. Synaptic activation that induces long-term potentiation caused a transient PAP motility increase leading to an enhanced astrocytic coverage of the synapse. Selective activation of calcium signals in individual PAPs using exogenous metabotropic receptor expression and two-photon uncaging reproduced these effects and enhanced spine stability. In vivo imaging in the somatosensory cortex of adult mice revealed that increased neuronal activity through whisker stimulation similarly elevates PAP movement. This in vivo PAP motility correlated with spine coverage and was predictive of spine stability. Conclusions: This study identifies a novel bidirectional interaction between synapses and astrocytes, in which synaptic activity and synaptic potentiation regulate PAP structural plasticity, which in turn determines the fate of the synapse. This mechanism may represent an important contribution of astrocytes to learning and memory processes.

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Section: Activation Of Paps At Single Synapses Increases Spine Coveramentioning

confidence: 99%

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

et al. 2014

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“…Here the hydroxyl group of Tyr forms an interhelical hydrogen bond with a backbone carbonyl group of C218 in TM6. The mMrgA1 has the same interaction with these homologous residues, but in the apo mMrgC11 receptor this conserved Tyr residue participates in aromatic interactions in TM regions [11].…”

Section: Resultsmentioning

confidence: 99%

“…Starting with the 3-D structures for mMrgC11 and mMrgA1 [11] as templates, we used MODELLER6v2 (University of California San Francisco, San Francisco, CA) to build a homology model for the 3-D structure of rMrgA receptor. The sequence of rMrgA receptor (TrEMBL accession number: Q7TN49) was aligned with mMrgC11 (TrEMBL accession number: Q8CIP3) and mMrgA1 (TrEMBL accession number: Q91WW5) using Clustal-W (version 1.82) [12] as shown in Fig.…”

Section: Molecular Modeling Of Receptor Structurementioning

confidence: 99%

“…The TM regions have 44 to 76 % identity (totaling 56 %) between rMrgA and mMrgC11 and 77 ~ 88 % identity between rMrgA and mMrgA1 (totaling 83 %). The mMrgC11 and mMrgA1 structures were predicted [11] using the MembStruk computational protocol, and validated by 1. using the HierDock computational protocol to predict the binding site for a series of tetrapeptides established experimentally to bind (~100 nM), 2. identifying the critical residues for binding these ligands,…”

Section: Molecular Modeling Of Receptor Structurementioning

confidence: 99%

“…For mMrgC11 the di-and tetra-peptide agonists were both predicted to bind to in the TM3-4-5-6 pocket [11]. Asn146 (TM4) is homologous to Asp161 in mMrgC11, which was identified as a key residue in ligand binding.…”

Section: Predicted Binding Site Of Adeninementioning

confidence: 99%

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Prediction of the 3-D structure of rat MrgA G protein-coupled receptor and identification of its binding site

Heo

Vaidehi

Wendel

et al. 2007

Journal of Molecular Graphics and Modelling

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Mrg receptors are orphan G protein-coupled receptors (GPCRs) located mainly at the specific set of sensory neurons in the dorsal root ganglia, suggesting a role in nociception. We report here the 3-D structure of rat MrgA (rMrgA) receptor [obtained from homology modeling to the recently validated predicted structures of mouse MrgA1 and MrgC11] and the structure of adenine (a known agonist, K i =18nM) bound to rMrgA. This predicted binding site is located within transmembrane helical domains (TMs) 3, 4, 5 and 6, with Asn residues in TM3 and TM4 identified as the key residues for adenine binding. Here the side chain of Asn88 (TM3) forms two pairs of hydrogen bonds with N3 and N9 of adenine while Asn146 (TM4) makes two pairs of hydrogen bonds with N1 and N6 of adenine. These interactions lock adenine tightly in the binding pocket. We also predict the binding site of guanine (not an agonist) and seven other derivatives. Guanine cannot make the hydrogen bond to Asn146 (TM4), leading to binding too weak to be observed experimentally. The predicted binding affinity for other adenine derivatives correlates with the availability of the hydrogen bonds to these two Asn residues. These results validate the predicted structure for rat MrgA and suggest mutation experiments that could further validate the structure. Moreover the predicted structure and binding site should be useful for seeking other small molecule agonists and antagonists.

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Prediction of the Three‐Dimensional Structure for the Rat Urotensin II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic Simulations

Kim

Park

et al. 2010

ChemMedChem

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Urotensin-II (U-II) has been shown to be the most potent mammalian vasoconstrictor known.[1, 2] Thus a U-II antagonist might be of therapeutic value in a number of cardiovascular disorders.[3] However, interspecies variability of several nonpeptidic ligands complicates the interpretation of in vivo studies of such antagonists in pre-clinical animal models of disease. Thus compound ACT058362 is a selective antagonist for human U-II receptor (hUT2R) with a reported Kd ~ 4 nM in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with Kd ~ 1,500 nM.[4] In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (Kd: ~ 9 nM) and rUT2R (Kd: ~ 21 nM).[3] To understand the species selectivity of the UT2R, we investigated the binding site of ACT058362 and SB706375 complex with both hUT2R and rUT2R to explain the dramatic (~ 400-fold) lower affinity of ACT058362 for rUT2R and the similar (~10 nM) affinity of SB706375 for both UT2R. These studies.used MembStruk and MSCDock to predict the UT2R structure and the binding site for ACT058362 and SB706375. Based on binding energy, we found two binding modes each with D1303.32 as the crucial anchoring point. We predict that ACT058362 (an aryl-amine-aryl or ANA ligand) binds in the TM 3456 region while we predict that SB706375 (an aryl-aryl-amine or AAN ligand) binds in the TM 1237 region. These predicted sites explain the known differences in binding the ANA ligand to rat and human while explaining the similar binding of the AAN compound to rat and human. Moreover the predictions explain currently available SAR data. To further validate the predicted binding site of these ligands to hUT2R and rUT2R, we propose several mutations that would help define the structural origins of differential responses of UT2R among species potentially indicating novel UT2R antagonists with cross-species high affinity.

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Prediction of the 3D Structure of FMRF‐amide Neuropeptides Bound to the Mouse MrgC11 GPCR and Experimental Validation

Cited by 24 publications

References 34 publications

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

Activity-Dependent Structural Plasticity of Perisynaptic Astrocytic Domains Promotes Excitatory Synapse Stability

Prediction of the 3-D structure of rat MrgA G protein-coupled receptor and identification of its binding site

Prediction of the Three‐Dimensional Structure for the Rat Urotensin II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic Simulations

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