Structural Studies of GABAA Receptor Binding Sites: Which Experimental Structure Tells us What?

Atomic resolution structures of cys-loop receptors, including one of a γ-aminobutyric acid type A receptor (GABA(A) receptor) subtype, allow amazing insights into the structural features and conformational changes that these pentameric ligand-gated ion channels (pLGICs) display. Here we present a comprehensive analysis of more than 30 cys-loop receptor structures of homologous proteins that revealed several allosteric binding sites not previously described in GABA(A) receptors. These novel binding sites were examined in GABA(A) receptor homology models and assessed as putative candidate sites for allosteric ligands. Four so far undescribed putative ligand binding sites were proposed for follow up studies based on their presence in the GABA(A) receptor homology models. A comprehensive analysis of conserved structural features in GABA(A) and glycine receptors (GlyRs), the glutamate gated ion channel, the bacterial homologs Erwinia chrysanthemi (ELIC) and Gloeobacter violaceus GLIC, and the serotonin type 3 (5-HT(3)) receptor was performed. The conserved features were integrated into a master alignment that led to improved homology models. The large fragment of the intracellular domain that is present in the structure of the 5-HT(3) receptor was utilized to generate GABA(A) receptor models with a corresponding intracellular domain fragment. Results of mutational and photoaffinity ligand studies in GABA(A) receptors were analyzed in the light of the model structures. This led to an assignment of candidate ligands to two proposed novel pockets, candidate binding sites for furosemide and neurosteroids in the trans-membrane domain were identified. The homology models can serve as hypotheses generators, and some previously controversial structural interpretations of biochemical data can be resolved in the light of the presented multi-template approach to comparative modeling. Crystal and cryo-EM microscopic structures of the closest homologs that were solved in different conformational states provided important insights into structural rearrangements of binding sites during conformational transitions. The impact of structural variation and conformational motion on the shape of the investigated binding sites was analyzed. Rules for best template and alignment choice were obtained and can generally be applied to modeling of cys-loop receptors. Overall, we provide an updated structure based view of ligand binding sites present in GABA(A) receptors

Measurement of proton electromagnetic form factors in e+e−→ppˉe^+e^- \to p\bar{p} in the energy region 2.00-3.08 GeV

The process of $e^+e^- \rightarrow p\bar{p}$ is studied at 22 center-of-mass energy points ($\sqrt{s}$) from 2.00 to 3.08 GeV, exploiting 688.5~pb$^{-1}$ of data collected with the BESIII detector operating at the BEPCII collider. The Born cross section~($\sigma_{p\bar{p}}$) of $e^+e^- \rightarrow p\bar{p}$ is measured with the energy-scan technique and it is found to be consistent with previously published data, but with much improved accuracy. In addition, the electromagnetic form-factor ratio ($|G_{E}/G_{M}|$) and the value of the effective ($|G_{\rm{eff}}|$), electric ($|G_E|$) and magnetic ($|G_M|$) form factors are measured by studying the helicity angle of the proton at 16 center-of-mass energy points. $|G_{E}/G_{M}|$ and $|G_M|$ are determined with high accuracy, providing uncertainties comparable to data in the space-like region, and $|G_E|$ is measured for the first time. We reach unprecedented accuracy, and precision results in the time-like region provide information to improve our understanding of the proton inner structure and to test theoretical models which depend on non-perturbative Quantum Chromodynamics

Measurement of the e+e−→π+π−\mathrm e^+\mathrm e^-\rightarrow\mathrm\pi^+\mathrm\pi^- Cross Section between 600 and 900 MeV Using Initial State Radiation

We extract the $e^+e^-\rightarrow \pi^+\pi^-$ cross section in the energy range between 600 and 900 MeV, exploiting the method of initial state radiation. A data set with an integrated luminosity of 2.93 fb$^{-1}$ taken at a center-of-mass energy of 3.773 GeV with the BESIII detector at the BEPCII collider is used. The cross section is measured with a systematic uncertainty of 0.9%. We extract the pion form factor $|F_\pi|^2$ as well as the contribution of the measured cross section to the leading order hadronic vacuum polarization contribution to $(g-2)_\mu$. We find this value to be $a_\mu^{\pi\pi,\rm LO}(600-900\;\rm MeV) = (368.2 \pm 2.5_{\rm stat} \pm 3.3_{\rm sys})\cdot 10^{-10}$.Comment: 14 pages, 7 figures, accepted by PL

Observation of the WW-Annihilation Decay Ds+→ωπ+D^{+}_{s} \rightarrow \omega \pi^{+} and Evidence for Ds+→ωK+D^{+}_{s} \rightarrow \omega K^{+}

We report on the observation of the $W$-annihilation decay $D^{+}_{s} \rightarrow \omega \pi^{+}$ and the evidence for $D_{s}^{+} \rightarrow \omega K^{+}$ with a data sample corresponding to an integrated luminosity of 3.19 fb$^{-1}$ collected with the BESIII detector at the center-of-mass energy $\sqrt{s} = 4.178$ GeV. We obtain the branching fractions $\mathcal{B}(D^{+}_{s} \rightarrow \omega \pi^{+}) = (1.77\pm0.32_{{\rm stat.}}\pm0.11_{{\rm sys.}}) \times 10^{-3}$ and $\mathcal{B}(D^{+}_{s} \rightarrow \omega K^{+}) = (0.87\pm0.24_{{\rm stat.}}\pm0.07_{{\rm sys.}}) \times 10^{-3}$, respectively

Precision measurement of the D∗0D^{*0} decay branching fractions

Using 482 pb$^{-1}$ of data taken at $\sqrt{s}=4.009$ GeV, we measure the branching fractions of the decays of $D^{*0}$ into $D^0\pi^0$ and $D^0\gamma$ to be \BR(D^{*0} \to D^0\pi^0)=(65.5\pm 0.8\pm 0.5)% and \BR(D^{*0} \to D^0\gamma)=(34.5\pm 0.8\pm 0.5)% respectively, by assuming that the $D^{*0}$ decays only into these two modes. The ratio of the two branching fractions is \BR(D^{*0} \to D^0\pi^0)/\BR(D^{*0} \to D^0\gamma) =1.90\pm 0.07\pm 0.05, which is independent of the assumption made above. The first uncertainties are statistical and the second ones systematic. The precision is improved by a factor of three compared to the present world average values

Observation of ηc→ωω\eta_c\to\omega\omega in J/ψ→γωωJ/\psi\to\gamma\omega\omega

Using a sample of $(1310.6\pm7.0)\times10^6$ $J/\psi$ events recorded with the BESIII detector at the symmetric electron positron collider BEPCII, we report the observation of the decay of the $(1^1 S_0)$ charmonium state $\eta_c$ into a pair of $\omega$ mesons in the process $J/\psi\to\gamma\omega\omega$. The branching fraction is measured for the first time to be $\mathcal{B}(\eta_c\to\omega\omega)= (2.88\pm0.10\pm0.46\pm0.68)\times10^{-3}$, where the first uncertainty is statistical, the second systematic and the third is from the uncertainty of $\mathcal{B}(J/\psi\to\gamma\eta_c)$. The mass and width of the $\eta_c$ are determined as $M=(2985.9\pm0.7\pm2.1)\,$MeV/$c^2$ and $\Gamma=(33.8\pm1.6\pm4.1)\,$MeV.Comment: 13 pages, 6 figure

Measurement of the Matrix Elements for the Decays η→π+π−π0\eta \rightarrow \pi^{+}\pi^{-}\pi^0 and η/η′→π0π0π0\eta/\eta^{\prime}\rightarrow\pi^0\pi^0\pi^0

Based on a sample of $1.31 \times 10^9$ $J/\psi$ events collected with the BESIII detector at the BEPCII collider, Dalitz plot analyses of selected 79,625 $\eta\rightarrow\pi^{+}\pi^{-}\pi^0$ events, 33,908 $\eta\rightarrow\pi^0\pi^0\pi^0$ events and 1,888 $\eta^{\prime}\rightarrow\pi^0\pi^0\pi^0$ events are performed. The measured matrix elements of $\eta\rightarrow\pi^+\pi^-\pi^0$ are in reasonable agreement with previous measurements. The Dalitz plot slope parameters of $\eta\rightarrow\pi^0\pi^0\pi^0$ and $\eta^{\prime}\rightarrow\pi^0\pi^0\pi^0$ are determined to be $-0.055 \pm 0.014 \pm 0.004$ and $-0.640 \pm 0.046 \pm 0.047$, respectively, where the first uncertainties are statistical and the second systematic. Both values are consistent with previous measurements, while the precision of the latter one is improved by a factor of three. Final state interactions are found to have an important role in those decays.Comment: 12 pages, 7 figure

Measurement of B(ψ(3770)→γχc1)\mathcal B(\psi(3770)\to\gamma \chi_{c1}) and search for ψ(3770)→γχc2\psi(3770)\to\gamma \chi_{c2}

We report a measurement of the branching fraction of $\psi(3770)\to\gamma\chi_{c1}$ and search for the transition $\psi(3770)\rightarrow \gamma \chi_{c2}$ based on 2.92~fb$^{-1}$ of $e^+e^-$ data accumulated at $\sqrt{s}=3.773$~GeV with the BESIII detector at the BEPCII collider. The measured branching fraction of $\psi(3770) \rightarrow \gamma \chi_{c1}$ is $\mathcal B(\psi(3770) \rightarrow \gamma \chi_{c1})=(2.48 \pm 0.15 \pm 0.23) \times 10^{-3}$, which is the most precise measurement to date. The upper limit on the branching fraction of $\psi(3770)\rightarrow \gamma \chi_{c2}$ at a $90\%$ confidence level is $\mathcal B(\psi(3770) \rightarrow \gamma \chi_{c2})<0.64 \times 10^{-3}$. The corresponding partial widths are $\Gamma(\psi(3770) \to \gamma \chi_{c1}) =(67.5\pm 4.1\pm 6.7)$~keV and $\Gamma(\psi(3770) \to \gamma \chi_{c2}) < 17.4$~keV