Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2

Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors

Loop-Generated Bounds on Changes to the Graviton Dispersion Relation

We identify the effective theory appropriate to the propagation of massless bulk fields in brane-world scenarios, to show that the dominant low-energy effect of asymmetric warping in the bulk is to modify the dispersion relation of the effective 4-dimensional modes. We show how such changes to the graviton dispersion relation may be bounded through the effects they imply, through loops, for the propagation of standard model particles. We compute these bounds and show that they provide, in some cases, the strongest constraints on nonstandard gravitational dispersions. The bounds obtained in this way are the strongest for the fewest extra dimensions and when the extra-dimensional Planck mass is the smallest. Although the best bounds come for warped 5-D scenarios, for which the 5D Planck Mass is O(TeV), even in 4 dimensions the graviton loop can lead to a bound on the graviton speed which is comparable with other constraints.Comment: 18 pages, LaTeX, 4 figures, uses revte

Livestock grazing and biodiversity : effects on CO2 exchange in semi-arid Karoo ecosystems, South Africa

DATA AVAILABILITY : Data used in this study can be obtained upon request and will be made available through the FLUXNET database.Livestock use in semi-arid South African ecosystems has not been extensively studied in relation to the Net Ecosystem Exchange (NEE) of carbon dioxide (CO2). We present four years of measurements from twinned eddy-covariance towers in Nama-Karoo, South Africa, to investigate the carbon fluxes and the impact of grazing intensity on NEE. The design contrasted NEE at a long-term site grazed at recommended levels (LG) with a long-term heavily grazed (EG) site that had been rested for 10 years, and was monitored for two years after which intensive grazing was reintroduced for this experiment. This allowed for the quantification of long-term NEE trends on “recovering” vegetations (years I, II) and short-term responses to an intensified land use (years III, IV). The results showed that the net release of CO2 was slightly higher at LG than on “recovering” vegetation at the EG site, where near-neutral exchange was observed during years I and II. However, after grazing was reintroduced to the EG site, differences between sites was reduced but not eliminated. These findings suggest that there is a somewhat higher carbon sequestration potential at the resting EG site than at the LG site, apparently associated with the dominance of unpalatable drought-tolerant grass species and local elimination of many palatable shrubs. Reduction of this sink potential by reintroduction of high-intensity grazing indicates the sensitivity of C-sequestration in this “recovering” system to heavy grazing, but underlines continued resilience of NEE under far heavier grazing than in the LG system. These data suggest notable trade-offs in these ecosystems between carbon storage, biodiversity, and livestock production with rainfall variability being a critical inter-annual driver.This study suggests that long-term resting of previously over-utilized southern African semi-arid vegetation supports enhanced carbon sequestration potential, even if over-utilization has transformed vegetation composition (i.e. has caused degradation through reduced plant species richness). However, this enhanced carbon sequestration potential can be quickly negated by the reintroduction of grazing, even after 10 years of resting. Achievement of carbon sequestration is dependent on average to above-average precipitation and its distribution throughout the year, with sink activity evident mainly after seasonal rains during the warm season.he German Federal Ministry of Education and Research (BMBF), research programs SPACES and SPACES II (Science Partnerships for the Assessment of Complex Earth System Processes in Southern Africa), projects ARS AfricaE and EMSAfrica.https://www.elsevier.com/locate/scitotenvhj2024Geography, Geoinformatics and MeteorologySDG-15:Life on lan

Light curves of five type Ia supernovae at intermediate redshift

We present multi-band light curves and distances for five type Ia supernovae at intermediate redshifts, 0.18<z<0.27. Three telescopes on the Canary Island of La Palma, INT, NOT and JKT, were used for discovery and follow-up of type Ia supernovae in the g' and r' filters. Supernova fluxes were measured by simultaneously fitting a supernova and host galaxy model to the data, and then calibrated using star catalogues from the Sloan Digital Sky Survey. The light curve peak luminosities, corrected for light curve shape and colour, are consistent with the expectations for a flat LambdaCDM universe at the 1.5-sigma level. One supernova in the sample, SN1999dr, shows surprisingly large reddening, considering that it is both located at a significant distance from the core of its host (~4 times the fitted exponential radius) and that the galaxy can be spectroscopically classified as early-type with no signs of ongoing star formation.Comment: 11 pages, 6 figures, updated to comply with referee comments, accepted for publication in A&

Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2

Conformational selection by small molecules expands inhibitory possibilities for protein kinases. Nuclear magnetic resonance (NMR) measurements of the mitogen-activated protein (MAP) kinase ERK2 have shown that activation by dual phosphorylation induces global motions involving exchange between two states, L and R. We show that ERK inhibitors Vertex-11e and SCH772984 exploit the small energetic difference between L and R to shift the equilibrium in opposing directions. An X-ray structure of active 2P-ERK2 complexed with AMP-PNP reveals a shift in the Gly-rich loop along with domain closure to position the nucleotide in a more catalytically productive conformation relative to inactive 0P-ERK2:ATP. X-ray structures of 2P-ERK2 complexed with Vertex-11e or GDC-0994 recapitulate this closure, which is blocked in a complex with a SCH772984 analog. Thus, the L→R shift in 2P-ERK2 is associated with movements needed to form a competent active site. Solution measurements by hydrogen-exchange mass spectrometry (HX-MS) reveal distinct binding interactions for Vertex-11e, GDC-0994, and AMP-PNP with active vs. inactive ERK2, where the extent of HX protection correlates with R state formation. Furthermore, Vertex-11e and SCH772984 show opposite effects on HX near the activation loop. Consequently, these inhibitors differentially affect MAP kinase phosphatase activity toward 2P-ERK2. We conclude that global motions in ERK2 reflect conformational changes at the active site that promote productive nucleotide binding and couple with changes at the activation loop to allow control of dephosphorylation by conformationally selective inhibitors

Improved photometric calibration of the SNLS and the SDSS supernova surveys

Context. We present a combined photometric calibration of the Supernova Legacy Survey (SNLS) and the SDSS supernova survey, which results from a joint effort of the SDSS and the SNLS collaborations. Aims. Our primary motivation is to eventually sharpen cosmological constraints derived from type Ia supernova measurements by improving the accuracy of the photometric calibration. We deliver fluxes calibrated to the HST spectrophotometric star network for large sets of tertiary stars that cover the science fields of both surveys in all photometric bands. We also cross-calibrate directly the two surveys and demonstrate their consistency. Methods. For each survey the flat-fielding is revised based on the analysis of dithered star observations. The calibration transfer from the HST spectrophotometric standard stars to the multi-epoch tertiary standard star catalogs in the science fields follows three different paths: observations of primary standard stars with the SDSS PT telescope; observations of Landolt secondary standard stars with SNLS MegaCam instrument at CFHT; and direct observation of faint HST standard stars with MegaCam. In addition, the tertiary stars for the two surveys are cross-calibrated using dedicated MegaCam observations of stripe 82. This overlap enables the comparison of these three calibration paths and justifies using their combination to improve the calibration accuracy. Results. Flat-field corrections have improved the uniformity of each survey as demonstrated by the comparison of photometry in overlapping fields: the rms of the difference between the two surveys is 3 mmag in gri, 4 mmag in z and 8 mmag in u. We also find a remarkable agreement (better than 1%) between the SDSS and the SNLS calibration in griz. The cross-calibration and the introduction of direct calibration observations bring redundancy and strengthen the confidence in the resulting calibration. We conclude that the surveys are calibrated to the HST with a precision of about 0.4% in griz. This precision is comparable to the external uncertainty affecting the color of the HST primary standard stars