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The multistep PROTAC (PROteolysis TArgeting Chimeras) degradation process poses challenges for their rational development, as rate limiting steps determining PROTAC efficiency remain largely unknown. Moreover, the slow throughput of currently used endpoint assays does not allow the comprehensive analysis of larger series of PROTACs. Here we developed cell-based assays using NanoLuciferase and HaloTags, that allow measuring PROTAC induced degradation and ternary complex formation kinetics and stability in cells. Using PROTACs developed for degradation of WDR5, the characterization of the mode of action of these PROTACs in the early degradation cascade revealed a key role of ternary complex formation and stability. Comparing a series of ternary complex crystal structures highlighted the importance of an efficient E3-target interface for ternary complex stability. The developed assays outline a strategy for the rational optimization of PROTACs using a series of live cell assays monitoring key steps of the early PROTAC induced degradation pathway.
Significance The multistep PROTAC induced degradation process of a POI poses a significant challenge for the rational design of these bifunctional small molecules as critical steps that limit PROTAC efficacy cannot be easily assayed at required throughput. In addition, the cellular location of the POI may pose additional challenges as some cellular compartments, such as the nucleus, may not be easily reached by PROTAC molecules and the targeted E3 ligases may not be present in this cellular compartment. We propose therefore a comprehensive assay panel for PROTACs evaluation in cellular environments using a sensor system that allows continuous monitoring of the protein levels of the endogenous POI. We developed a cell line expressing WDR5 from its endogenous locus in fusion with a small sequence tag (HiBIT) that can be reconstituted to functional NanoLuciferase (NLuc). This system allowed continuous monitoring of endogenous WDR5 levels in cells and together with HaloTag system also the continuous monitoring of ternary complex (E3, WDR5 and PROTAC) formation. As this assay can be run at high throughput, we used this versatile system monitoring three diverse chemical series of WDR5 PROTACs that markedly differ in their degradation properties. Monitoring cell penetration, binary complex formation (PROTAC-WDR5 and PROTAC-VHL) as well as ternary complex formation we found that PROTAC efficiency highly correlated with synergy of ternary complex formation in cells. This study represents a first data set on diverse PROTACs studying this property in cellulo and it outlines a strategy for the rational optimization of PROTACs. It also provided kinetic data on ternary complex assembly and dissociation that may serve as a benchmark for future studies utilizing also kinetic properties for PROTAC development. Comparative structural studies revealed larger PROTAC mediated interaction surfaces for PROTACs that efficiently formed ternary complexes highlighting the utility of structure based optimization of PROTAC induced ternary complexes in the development process.
Type-II multiferroic materials, in which ferroelectric polarization is induced by inversion non-symmetric magnetic order, promise new and highly efficient multifunctional applications based on mutual control of magnetic and electric properties. However, to date this phenomenon is limited to low temperatures. Here we report giant pressure-dependence of the multiferroic critical temperature in CuBr2: at 4.5 GPa it is enhanced from 73.5 to 162 K, to our knowledge the highest TC ever reported for non-oxide type-II multiferroics. This growth shows no sign of saturating and the dielectric loss remains small under these high pressures. We establish the structure under pressure and demonstrate a 60\% increase in the two-magnon Raman energy scale up to 3.6 GPa. First-principles structural and magnetic energy calculations provide a quantitative explanation in terms of dramatically pressure-enhanced interactions between CuBr2 chains. These large, pressure-tuned magnetic interactions motivate structural control in cuprous halides as a route to applied high-temperature multiferroicity.
The elliptic, v2, triangular, v3, and quadrangular, v4, azimuthal anisotropic flow coefficients are measured for unidentified charged particles, pions, and (anti-)protons in Pb–Pb collisions at √sNN=2.76 TeV with the ALICE detector at the Large Hadron Collider. Results obtained with the event plane and four-particle cumulant methods are reported for the pseudo-rapidity range |η|<0.8 at different collision centralities and as a function of transverse momentum, pT, out to pT=20 GeV/c. The observed non-zero elliptic and triangular flow depends only weakly on transverse momentum for pT>8 GeV/c. The small pT dependence of the difference between elliptic flow results obtained from the event plane and four-particle cumulant methods suggests a common origin of flow fluctuations up to pT=8 GeV/c. The magnitude of the (anti-)proton elliptic and triangular flow is larger than that of pions out to at least pT=8 GeV/c indicating that the particle type dependence persists out to high pT.
Harmonic decomposition of two particle angular correlations in Pb–Pb collisions at √sNN=2.76 TeV
(2012)
Angular correlations between unidentified charged trigger (t) and associated (a) particles are measured by the ALICE experiment in Pb–Pb collisions at √sNN=2.76 TeV for transverse momenta 0.25<pTt,a<15 GeV/c, where pTt>pTa. The shapes of the pair correlation distributions are studied in a variety of collision centrality classes between 0 and 50% of the total hadronic cross section for particles in the pseudorapidity interval |η|<1.0. Distributions in relative azimuth Δϕ≡ϕt−ϕa are analyzed for |Δη|≡|ηt−ηa|>0.8, and are referred to as “long-range correlations”. Fourier components VnΔ≡〈cos(nΔϕ)〉 are extracted from the long-range azimuthal correlation functions. If particle pairs are correlated to one another through their individual correlation to a common symmetry plane, then the pair anisotropy VnΔ(pTt,pTa) is fully described in terms of single-particle anisotropies vn(pT) as VnΔ(pTt,pTa)=vn(pTt)vn(pTa). This expectation is tested for 1⩽n⩽5 by applying a global fit of all VnΔ(pTt,pTa) to obtain the best values vn{GF}(pT). It is found that for 2⩽n⩽5, the fit agrees well with data up to pTa∼3–4 GeV/c, with a trend of increasing deviation as pTt and pTa are increased or as collisions become more peripheral. This suggests that no pair correlation harmonic can be described over the full 0.25<pT<15 GeV/c range using a single vn(pT) curve; such a description is however approximately possible for 2⩽n⩽5 when pTa<4 GeV/c. For the n=1 harmonic, however, a single v1(pT) curve is not obtained even within the reduced range pTa<4 GeV/c.
An experiment addressing electron capture (EC) decay of hydrogen-like 142Pm60+ions has been conducted at the experimental storage ring (ESR) at GSI. The decay appears to be purely exponential and no modulations were observed. Decay times for about 9000 individual EC decays have been measured by applying the single-ion decay spectroscopy method. Both visually and automatically analysed data can be described by a single exponential decay with decay constants of 0.0126(7)s−1 for automatic analysis and 0.0141(7)s−1 for manual analysis. If a modulation superimposed on the exponential decay curve is assumed, the best fit gives a modulation amplitude of merely 0.019(15), which is compatible with zero and by 4.9 standard deviations smaller than in the original observation which had an amplitude of 0.23(4).
A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.