G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and ...structural dynamics remains largely unknown. Frizzled 6 (FZD
) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD
dimerizes and that the dimer interface of FZD
is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD
mutant indicates that dimer dissociation is an integral part of FZD
signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.Frizzled 6 (FZD
) is a G protein-coupled receptor (GPCR) involved in several cellular processes. Here, the authors use live cell imaging and spectroscopy to show that FZD
forms dimers, whose association is regulated by WNT proteins and that dimer dissociation is crucial for FZD
signaling.
Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi‐target profiles is rarely pursued because ...it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure‐based strategy to identify dual‐target ligands of G‐protein‐coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chemical library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure‐based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual‐target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism.
Structure‐based modelling was used to design a single compound with the ability to modulate the activity of two G‐protein‐coupled receptors relevant for Parkinson's disease. The most potent scaffold displayed nanomolar binding affinities for both targets and was active in a rat model of parkinsonism.
Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The ...interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y2502.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, impaired in DVL2 binding, was defective in both β-catenin-dependent and β-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gα12 and Gα13 and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y2502.39 is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y2502.39 and H3484.46 plays a role in specifying downstream signaling pathways induced by the receptor.
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•Y2502.39 in the FZD4 intracellular loop 1 is crucial for interaction with DVL2.•Interaction of Y2502.39, H3484.46 and W3524.50 is important for FZD-DVL interaction.•FZD4-Y2502.39F is defective in signaling through DVL.•FZD4-Y2502.39F maintains FZD4-G protein signaling.•Results suggest that FZDs can be biased towards individual signaling pathways.
The Liquid Argon calorimeters play a central role in the ATLAS experiment. The environment at the LHC collider imposes challenging tasks to their read-out system. To achieve measurements of particles ...and trigger signals at high precision, the detector signals are processed at various stages before reaching the Data Acquisition system (DAQ). Signals from the calorimeter cells are received by front-end boards, which digitize and sample the incoming pulse. Read-out Driver (ROD) boards further process the data at a trigger rate of up to 75 kHz. An optimal filtering procedure is applied to optimize the signal-to-noise ratio. The ROD boards calculate precise energy, time and quality of the detector pulse, which are then sent to the DAQ. In addition, the RODs perform a monitoring of the data. The architecture of the ATLAS Liquid Argon detector read-out is discussed, in particular the design and functionality of the ROD board. Performance results obtained with ROD prototypes as well as experience from complete test setups with final production boards are reported.
A search for excited states of the Bc+/- meson is performed using 4.9 inv. fb of 7 TeV and 19.2 inv. fb of 8 TeV pp collision data collected by the ATLAS experiment at the LHC. A new state is ...observed through its hadronic transition to the ground state, with the latter detected in the decay Bc+/- --> J/psi pi+/-. The state appears in the m(Bc+/- pi+ pi-) - m(Bc+/-) - 2m(pi+/-) mass difference distribution with a significance of 5.2 standard deviations. The mass of the observed state is 6842 +/- 4 +/- 5 MeV, where the first error is statistical and the second is systematic. The mass and decay of this state are consistent with expectations for the second S-wave state of the Bc, Bc(2S).
A search is presented for direct top-squark pair production in final states with two leptons (electrons or muons) of opposite charge using 20.3fb-1 of pp collision data at sqrt(s)=8TeV, collected by ...the ATLAS experiment at the Large Hadron Collider in 2012. No excess over the Standard Model expectation is found. The results are interpreted under the separate assumptions (i) that the top squark decays to a b-quark in addition to an on-shell chargino whose decay occurs via a real or virtual W boson, or (ii) that the top squark decays to a t-quark and the lightest neutralino. A top squark with a mass between 150 GeV and 445 GeV decaying to a b-quark and an on-shell chargino is excluded at 95% confidence level for a top squark mass equal to the chargino mass plus 10 GeV, in the case of a 1 GeV lightest neutralino. Top squarks with masses between 215 (90) GeV and 530 (170) GeV decaying to an on-shell (off-shell) t-quark and a neutralino are excluded at 95% confidence level for a 1 GeV neutralino.
A search for the direct production of charginos and neutralinos in final states with three leptons and missing transverse momentum is presented. The analysis is based on 20.3 fb-1 of sqrt(s) = 8 TeV ...proton--proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with the Standard Model expectations and limits are set in R-parity-conserving phenomenological Minimal Supersymmetric Standard Models and in simplified supersymmetric models, significantly extending previous results. For simplified supersymmetric models of direct chargino ($\tilde\chi^\pm_1$) and next-to-lightest neutralino ($\tilde{\chi}_2^0$) production with decays to lightest neutralino ($\tilde{\chi}_1^0$) via either all three generations of sleptons, staus only, gauge bosons, or Higgs bosons, $\tilde\chi^\pm_1$ and $\tilde{\chi}_2^0$ masses are excluded up to 700 GeV, 380 GeV, 345 GeV, or 148 GeV respectively, for a massless $\tilde{\chi}_1^0$.
The inclusive top quark pair production cross-section has been measured in proton-proton collisions at sqrt(s)=7 TeV and sqrt(s)=8 TeV with the ATLAS experiment at the LHC, using ttbar events with an ...opposite-charge e-mu pair in the final state. The measurement was performed with the 2011 7 TeV dataset corresponding to an integrated luminosity of 4.6 fb-1 and the 2012 8 TeV dataset of 20.3 fb-1. The numbers of events with exactly one and exactly two b-tagged jets were counted and used to simultaneously determine sigma(ttbar) and the efficiency to reconstruct and b-tag a b-jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section was measured to be: sigma(ttbar)=$182.9\pm3.1\pm4.2\pm3.6\pm3.3$ pb (7 TeV) and sigma(ttbar)=$242.4\pm1.7\pm5.5\pm7.5\pm4.2$ pb (8 TeV), where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the knowledge of the integrated luminosity and of the LHC beam energy. The results are consistent with recent theoretical QCD calculations at NNLO. Fiducial measurements corresponding to the experimental acceptance of the leptons are also reported, together with the ratio of cross-sections measured at the two centre-of-mass energies. The inclusive cross-section results were used to determine the top quark pole mass via the dependence of the theoretically-predicted cross-section on $m_t^{pole}$, giving a result of $m_t^{pole}=172.9^{+2.5}_{-2.6}$ GeV. By looking for an excess of ttbar production with respect to the QCD prediction, the results were also used to place limits on the pair-production of supersymmetric top squarks with masses close to the top quark mass decaying to predominantly right-handed top quarks and a light neutralino, the lightest supersymmetric particle. Top squarks with masses between the top quark mass and 177 GeV are excluded at the 95% confidence level.
A measurement of the ZZ production cross section in proton-proton collisions at sqrt(s) = 7 TeV using data recorded by the ATLAS experiment at the Large Hadron Collider is presented. In a data sample ...corresponding to an integrated luminosity of 4.6 fb-1 collected in 2011, events are selected that are consistent either with two Z bosons decaying to electrons or muons or with one Z boson decaying to electrons or muons and a second Z boson decaying to neutrinos. The ZZ*->llll and ZZ->llnunu cross sections are measured in restricted phase-space regions. These results are then used to derive the total cross section for ZZ events produced with both Z bosons in the mass range 66 to 116 GeV, sigmaZZtot = 6.7 +-0.7 +0.4-0.3 +-0.3 pb, which is consistent with the Standard Model prediction of 5.89+0.22-0.18 pb calculated at next-to-leading order in QCD. The normalized differential cross sections in bins of various kinematic variables are presented. Finally, the differential event yield as a function of the transverse momentum of the leading Z boson is used to set limits on anomalous neutral triple gauge boson couplings in ZZ production.
A search is presented for production of a heavy up-type quark (t') together with its antiparticle, assuming a significant branching ratio for subsequent decay into a W boson and a b quark. The search ...is based on 4.7 fb^-1 of pp collisions at sqrt(s)=7 TeV recorded in 2011 with the ATLAS detector at the CERN Large Hadron Collider. Data are analyzed in the lepton+jets final state, characterized by a high-transverse-momentum isolated electron or muon, large missing transverse momentum and at least three jets. The analysis strategy relies on the substantial boost of the W bosons in the t't'bar signal when mt'>=400 GeV. No significant excess of events above the Standard Model expectation is observed and the result of the search is interpreted in the context of fourth-generation and vector-like quark models. Under the assumption of a branching ratio BR(t'->Wb)=1, a fourth-generation t' quark with mass lower than 656 GeV is excluded at 95% confidence level. In addition, in light of the recent discovery of a new boson of mass ~126 GeV at the LHC, upper limits are derived in the two-dimensional plane of BR(t'->Wb) versus BR(t'->Ht), where H is the Standard Model Higgs boson, for vector-like quarks of various masses.
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