Search

Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.

Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells. Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Φ)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet. Although atomic structures of protective antigen prepores are available, how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryo-electron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-A resolution. The structure reveals the long-sought-after catalytic Φ-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed.

Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells. Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Φ)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet. Although atomic structures of protective antigen prepores are available, how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryo-electron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-Å resolution. The structure reveals the long-sought-after catalytic Φ-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed.

The cover shows part of the Larry's Lookout panorama, seen from the Mars Exploration Rover (MER) Spirit during its drive up Husband Hill: the summit is about 200 metres from the rover. Six papers this week report in detail on the MER mission. An Analysis compares predictions used to select a landing site with the conditions actually encountered. This ‘ground truth’ will be invaluable for interpreting future remote-sensing data. Surface chemistry suggests that the upper layer of soil may contain 1% meteoritic material. MER provides a unique glimpse of solar transits of the moons Phobos and Deimos. Rover Opportunity examined wind-related processes, and spectroscopy indicates a dry origin for atmospheric dust. Features from within the Gusev crater give more information on the role of liquid water in Mars's past. An accompanying News and Views puts the MER data in context. Gusev crater was selected as the landing site for the Spirit rover because of the possibility that it once held a lake. Thus one of the rover's tasks was to search for evidence of lake sediments1. However, the plains at the landing site were found to be covered by a regolith composed of olivine-rich basaltic rock and windblown ‘global’ dust2. The analyses of three rock interiors exposed by the rock abrasion tool showed that they are similar to one another, consistent with having originated from a common lava flow3,4,5,6,7,8. Here we report the investigation of soils, rock coatings and rock interiors by the Spirit rover from sol (martian day) 1 to sol 156, from its landing site to the base of the Columbia hills. The physical and chemical characteristics of the materials analysed provide evidence for limited but unequivocal interaction between water and the volcanic rocks of the Gusev plains. This evidence includes the softness of rock interiors that contain anomalously high concentrations of sulphur, chlorine and bromine relative to terrestrial basalts and martian meteorites9; sulphur, chlorine and ferric iron enrichments in multilayer coatings on the light-toned rock Mazatzal; high bromine concentration in filled vugs and veins within the plains basalts; positive correlations between magnesium, sulphur and other salt components in trench soils; and decoupling of sulphur, chlorine and bromine concentrations in trench soils compared to Gusev surface soils, indicating chemical mobility and separation.

THE rearrangement of synaptic connections during normal and deprived development is thought to be controlled by correlations in afferent impulse activity1. A favoured model is based on postsynaptic detection of synchronously active afferents; synapses are stabilized when pre- and postsynaptic activity is correlated and weakened or eliminated when their activity is uncorrelated2,3. Most evidence for this model comes from demonstrations that correlated afferent input is necessary for the segregation of eye-dominant inputs in the developing vertebrate visual system1,4,5 and that critical period plasticity of ocular dominance columns in cat visual cortex is disrupted by blockade of postsynaptic transmission6–8. We tested whether the developmental plasticity of somatosensory columns, known as 'barrels', in rodent primary somatosensory cortex (S1)9–13 is similar to that of ocular dominance columns. We report here that the selective disruption of postsynaptic activation in rat S1 by application of a glutamate receptor antagonist inhibits rearrangements in the somatotopic patterning of thalamocorticalafferents induced by manipulations of the sensory periphery during the critical period. These findings show that postsynaptic activation has a prominent role in critical period plasticity in S1 cortex.

The earliest galaxies are expected to emerge in the first billion years of the Universe during the Epoch of Reionization. However, both the spectroscopic confirmation of photometrically-selected galaxies at this epoch and the characterization of their early dynamical state has been hindered by the lack of bright, accessible lines to probe the velocity structure of their interstellar medium. We present the first ALMA spectroscopic confirmation of such sources at z > 6 using the far-infrared [C II]{\lambda}157.74{\mu}m emission line, and, for the first time, measurement of the velocity structure, for two galaxies at z = 6.8540+/-0.0003 and z = 6.8076+/-0.0002. Remarkably, the [C II] line luminosity from these galaxies is higher than previously found in `normal' star-forming galaxies at z > 6.5. This suggests that we are sampling a part of the galaxy population different from the galaxies found through detection of the Ly{\alpha} line. The luminous and extended [C II] detections reveal clear velocity gradients that, if interpreted as rotation, would suggest these galaxies have turbulent, yet rotation-dominated disks, with similar stellar-to-dynamical mass fractions as observed for H{\alpha} emitting galaxies 2 Gyr later at cosmic noon. Our novel approach for confirming galaxies during Reionization paves the way for larger studies of distant galaxies with spectroscopic redshifts from ALMA. Particularly important, this opens up opportunities for high angular-resolution [C II] dynamics in galaxies less than one billion years after the Big Bang., Comment: 14 pages, 5 figures, 1 table, published in Nature (submitted version)