94 research outputs found
A community Biased Signaling Atlas
No full textBiased signaling gives hormones, probes or drugs distinct functional outcomes via the same receptor. The Biased Signaling Atlas (https://BiasedSignalingAtlas.org) provides a community hub with data and tools to advance this paradigm, which may yield safer and more potent drugs
Five-Membered N-Heterocyclic Scaffolds as Novel Amino Bioisosteres at γ-Aminobutyric Acid (GABA) Type A Receptors and GABA Transporters
No full textGiven the heterogeneity within the γ-aminobutyric acid (GABA) receptor and transporter families, a detailed insight into the pharmacology is still relatively sparse. To enable studies of the physiological roles governed by specific receptor and transporter subtypes, a series of GABA analogues comprising five-membered nitrogen- and sulfur-containing heterocycles as amine bioisosteres were synthesized and pharmacologically characterized at native and selected recombinant GABAA receptors and GABA transporters. The dihydrothiazole and imidazoline analogues, 5-7, displayed moderate GAT activities and GABAA receptor binding affinities in the mid-nanomolar range (Ki, 90-450 nM). Moreover, they exhibited full and equipotent agonist activity compared to GABA at GABAA-αβγreceptors but somewhat lower potency as partial agonists at the GABAA-ρ1 receptor. Stereoselectivity was observed for compounds 4 and 7 for the GABAA-αβγreceptors but not the GABAA-ρ1 receptor. This study illustrates how subtle differences in these novel amino GABA bioisosteres result in diverse pharmacological profiles in terms of selectivity and efficacy
QATAR-2 : a K dwarf orbited by a transiting hot Jupiter and a more massive companion in an outer orbit
No full textWe report the discovery and initial characterization of Qatar-2b, a hot Jupiter transiting a V = 13.3 mag K dwarf in a circular orbit with a short period, P b = 1.34 days. The mass and radius of Qatar-2b are M P = 2.49 M J and R P = 1.14 R J, respectively. Radial-velocity monitoring of Qatar-2 over a span of 153 days revealed the presence of a second companion in an outer orbit. The Systemic Console yielded plausible orbits for the outer companion, with periods on the order of a year and a companion mass of at least several M J. Thus, Qatar-2 joins the short but growing list of systems with a transiting hot Jupiter and an outer companion with a much longer period. This system architecture is in sharp contrast to that found by Kepler for multi-transiting systems, which are dominated by objects smaller than Neptune, usually with tightly spaced orbits that must be nearly coplanar
Crystal structure of the GLUA2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and ME-CX516 at 1.72 A resolution
No full textRational design of a heterotrimeric G protein α subunit with artificial inhibitor sensitivity
No full textTransmembrane signals initiated by a range of extracellular stimuli converge on members of the Gq family of heterotrimeric G proteins, which relay these signals in target cells. Gq family G proteins comprise Gq, G11, G14, and G16, which upon activation mediate their cellular effects via inositol lipid-dependent and -independent signaling to control fundamental processes in mammalian physiology. To date, highly specific inhibition of Gq/11/14 signaling can be achieved only with FR900359 (FR) and YM-254890 (YM), two naturally occurring cyclic depsipeptides. To further development of FR or YM mimics for other Gα subunits, we here set out to rationally design Gα16 proteins with artificial FR/YM sensitivity by introducing an engineered depsipeptide binding site. Thereby we permit control of G16 function through ligands that are inactive on the wild type protein. Using CRISPR/Cas9-generated Gαq/Gα11-null cells and loss- and gain-of-function mutagenesis along with label-free whole-cell biosensing, we determined the molecular coordinates for FR/YM inhibition of Gq and transplanted these to FR/YM-insensitive G16. Intriguingly, despite having close structural similarity, FR and YM yielded biologically distinct activities: it was more difficult to perturb Gq inhibition by FR and easier to install FR inhibition onto G16 than perturb or install inhibition with YM. A unique hydrophobic network utilized by FR accounted for these unexpected discrepancies. Our results suggest that non-Gq/11/14 proteins should be amenable to inhibition by FR scaffold-based inhibitors, provided that these inhibitors mimic the interaction of FR with Gα proteins harboring engineered FR-binding sites.</p
Crystal structure of the glua2 ligand-binding domain (S1S2J-L483Y-N754S) in complex with glutamate and CX516 at 2.0 A resolution
No full textOGLE 2008–BLG–290 : an accurate measurement of the limb darkening of a galactic bulge K giant spatially resolved by microlensing
No full textContext. Not only is gravitational microlensing a successful tool for discovering distant exoplanets, but it also enables characterization of the lens and source stars involved in the lensing event.
Aims. In high-magnification events, the lens caustic may cross over the source disk, which allows determination of the angular size of the source and measurement of its limb darkening.
Methods. When such extended-source effects appear close to maximum magnification, the resulting light curve differs from the characteristic Paczy´nski point-source curve. The exact shape of the light curve close to the peak depends on the limb darkening of the source. Dense photometric
coverage permits measurement of the respective limb-darkening coefficients.
Results. In the case of the microlensing event OGLE 2008-BLG-290, the K giant source star reached a peak magnification at about 100. Thirteen different telescopes have covered this event in eight different photometric bands. Subsequent light-curve analysis yielded measurements of linear limb-darkening coefficients of the source in six photometric bands. The best-measured coefficients lead to an estimate of the source effective temperature
of about 4700+100 −200 K. However, the photometric estimate from colour-magnitude diagrams favours a cooler temperature of 4200 ± 100 K.
Conclusions. Because the limb-darkening measurements, at least in the CTIO/SMARTS2 Vs- and Is-bands, are among the most accurate obtained, the above disagreement needs to be understood. A solution is proposed, which may apply to previous events where such a discrepancy also
appeared
High-precision photometry by telescope defocusing - IV. Confirmation of the huge radius of WASP-17 b
No full textpeer reviewedWe present photometric observations of four transits in the WASP-17 planetary system, obtained using telescope defocusing techniques and with scatters reaching 0.5 mmag per point. Our revised orbital period is 4.0 ± 0.6 s longer than previous measurements, a difference of 6.6σ, and does not support the published detections of orbital eccentricity in this system. We model the light curves using the JKTEBOP code and calculate the physical properties of the system by recourse to five sets of theoretical stellar model predictions. The resulting planetary radius, R[SUB]b[/SUB] = 1.932 ± 0.052 ± 0.010 R[SUB]Jup[/SUB] (statistical and systematic errors, respectively), provides confirmation that WASP-17 b is the largest planet currently known. All 14 planets with radii measured to be greater than 1.6 R[SUB]Jup[/SUB] are found around comparatively hot (T[SUB]eff[/SUB] > 5900 K) and massive (M[SUB]A[/SUB] > 1.15 M[SUB]&sun;[/SUB]) stars. Chromospheric activity indicators are available for eight of these stars, and all imply a low activity level. The planets have small or zero orbital eccentricities, so tidal effects struggle to explain their large radii. The observed dearth of large planets around small stars may be natural but could also be due to observational biases against deep transits, if these are mistakenly labelled as false positives and so not followed up. Based on data collected by MiNDSTEp with the Danish 1.54-m telescope at the ESO La Silla Observatory.Royal Society University Research Fellow
Realisation of a fully-deterministic microlensing observing strategy for inferring planet populations
No full textpeer reviewedWithin less than 15 years, the count of known planets orbiting stars other than the Sun has risen from none to more than 400 with detections arising from four successfully applied techniques: Doppler-wobbles, planetary transits, gravitational microlensing, and direct imaging. While the hunt for twin Earths is on, a statistically well-defined sample of the population of planets in all their variety is required for probing models of planet formation and orbital evolution so that the origin of planets that harbour life, like and including ours, can be understood. Given the different characteristics of the detection techniques, a complete picture can only arise from a combination of their respective results. Microlensing observations are well-suited to reveal statistical properties of the population of planets orbiting stars in either the Galactic disk or bulge from microlensing observations, but a mandatory requirement is the adoption of strictly-deterministic criteria for selecting targets and identifying signals. Here, we describe a fully-deterministic strategy realised by means of the ARTEMiS (Automated Robotic Terrestrial Exoplanet Microlensing Search) system at the Danish 1.54-m telescope at ESO La Silla between June and August 2008 as part of the MiNDSTEp (Microlensing Network for the Detection of Small Terrestrial Exoplanets) campaign, making use of immediate feedback on suspected anomalies recognized by the SIGNALMEN anomaly detector. We demonstrate for the first time the feasibility of such an approach, and thereby the readiness for studying planet populations down to Earth mass and even below, with ground-based observations. While the quality of the real-time photometry is a crucial factor on the efficiency of the campaign, an impairment of the target selection by data of bad quality can be successfully avoided. With a smaller slew time, smaller dead time, and higher through-put, modern robotic telescopes could significantly outperform the 1.54-m Danish, whereas lucky-imaging cameras could set new standards for high-precision follow-up monitoring of microlensing events. Based on data collected by the MiNDSTEp consortium with the Danish 1.54-m telescope at the ESO La Silla Observatory
Physical properties, transmission and emission spectra of the WASP-19 planetary system from multi-colour photometry
No full textpeer reviewedWe present new ground-based, multi-colour, broad-band photometric measurements of the physical parameters, transmission and emission spectra of the transiting extrasolar planet WASP-19b. The measurements are based on observations of eight transits and four occultations through a Gunn i filter using the 1.54-m Danish Telescope, 14 transits through an R[SUB]c[/SUB] filter at the Perth Exoplanet Survey Telescope (PEST) observatory and one transit observed simultaneously through four optical (Sloan g[SUP]'[/SUP], r[SUP]'[/SUP], i[SUP]'[/SUP], z[SUP]'[/SUP]) and three near-infrared (J, H, K) filters, using the Gamma Ray Burst Optical and Near-Infrared Detector (GROND) instrument on the MPG/ESO 2.2-m telescope. The GROND optical light curves have a point-to-point scatter around the best-fitting model between 0.52 and 0.65 mmag rms. We use these new data to measure refined physical parameters for the system. We find the planet to be more bloated (R[SUB]b[/SUB] = 1.410 ± 0.017R[SUB]Jup[/SUB]; M[SUB]b[/SUB] = 1.139 ± 0.030M[SUB]Jup[/SUB]) and the system to be twice as old as initially thought. We also used published and archived data sets to study the transit timings, which do not depart from a linear ephemeris. We detected an anomaly in the GROND transit light curve which is compatible with a spot on the photosphere of the parent star. The starspot position, size, spot contrast and temperature were established. Using our new and published measurements, we assembled the planet's transmission spectrum over the 370-2350 nm wavelength range and its emission spectrum over the 750-8000 nm range. By comparing these data to theoretical models we investigated the theoretically predicted variation of the apparent radius of WASP-19b as a function of wavelength and studied the composition and thermal structure of its atmosphere. We conclude that: (i) there is no evidence for strong optical absorbers at low pressure, supporting the common idea that the planet's atmosphere lacks a dayside inversion; (ii) the temperature of the planet is not homogenized, because the high warming of its dayside causes the planet to be more efficient in re-radiating than redistributing energy to the night side; (iii) the planet seems to be outside of any current classification scheme
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