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1 Molecular basis for pore blockade of human Na+ channel Nav1.2 by the {mu}-conotoxin KIIIA 2019-02-17             

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The voltage-gated sodium channel Nav1.2 is responsible for the initiation and propagation of action potentials in the central nervous system. We report the cryo–electron microscopy structure of human Nav1.2 bound to a peptidic pore blocker, the μ-conotoxin KIIIA, in the presence of an auxiliary subunit β2 to an overall resolution of 3.0 Å. The immunoglobulin (Ig) domain of β2 interacts with the shoulder of the pore domain through a disulfide bond. The 16-residue KIIIA interacts with the extracellular segments in repeats I to III, placing Lys7 at the entrance to the selectivity filter. Many interacting residues are specific to Nav1.2, revealing a molecular basis for KIIIA specificity. The structure establishes a framework for rational design of subtype-specific blockers for Nav channels.

2 Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins 2019-02-17             

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Voltage-gated sodium channel Nav1.7 represents a promising target for pain relief. Here we report the cryo-EM structures of the human Nav1.7-β1-β2 complex bound to two combinations of pore blockers and gating modifier toxins (GMTs), tetrodotoxin with Protoxin-II and saxitoxin with Huwentoxin-IV, both determined at overall resolutions of 3.2 Å. The two structures are nearly identical except for minor shifts of VSDII, whose S3-S4 linker accommodates the two GMTs in a similar manner. One additional Protoxin-II sits on top of the S3-S4 linker in VSDIV. The structures may represent an inactivated state with all four VSDs "up" and the intracellular gate closed. The structures illuminate the path toward mechanistic understanding of the function and disease of Nav1.7 and establish the foundation for structure-aided development of analgesics.

3 Parallel adaptation of rabbit populations to myxoma virus 2019-02-17             

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In the 1950s the myxoma virus was released into European rabbit populations in Australia and Europe, decimating populations and resulting in the rapid evolution of resistance. We investigated the genetic basis of resistance by comparing the exomes of rabbits collected before and after the pandemic. We found a strong pattern of parallel evolution, with selection on standing genetic variation favoring the same alleles in Australia, France and the United Kingdom. Many of these changes occurred in immunity-related genes, supporting a polygenic basis of resistance. We experimentally validated the role of several genes in viral replication and showed that selection acting on an interferon protein has increased its antiviral effect.

4 Efficient topological materials discovery using symmetry indicators 2019-02-12             

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Efficient topological materials discovery using symmetry indicators

Efficient topological materials discovery using symmetry indicators, Published online: 11 February 2019; doi:10.1038/s41567-019-0418-7

Symmetry labels of materials under certain space groups can be used to indicate their band topology. Integrating that into first-principles band-structure calculations, new topological materials with a diversity of topological phenomena are discovered.

5 Quantum error correction and universal gate set operation on a binomial bosonic logical qubit 2019-02-12             

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Quantum error correction and universal gate set operation on a binomial bosonic logical qubit

Quantum error correction and universal gate set operation on a binomial bosonic logical qubit, Published online: 11 February 2019; doi:10.1038/s41567-018-0414-3

Repeated error correction creates a logical qubit encoded in the hybrid state of a superconducting circuit and a bosonic cavity, which is shown to be fully controllable under a universal single-qubit gate set.

6 Spin–phonon interactions in silicon carbide addressed by Gaussian acoustics 2019-02-12             

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Spin–phonon interactions in silicon carbide addressed by Gaussian acoustics

Spin–phonon interactions in silicon carbide addressed by Gaussian acoustics, Published online: 11 February 2019; doi:10.1038/s41567-019-0420-0

The authors use surface acoustic waves, focused in a Gaussian geometry, to manipulate the spin state of divacancy defects in silicon carbide via mechanical driving. They demonstrate that shear strain is important in controlling the spin transitions.

7 Axial-field-induced chiral channels in an acoustic Weyl system 2019-02-12             

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Axial-field-induced chiral channels in an acoustic Weyl system

Axial-field-induced chiral channels in an acoustic Weyl system, Published online: 11 February 2019; doi:10.1038/s41567-019-0415-x

Axial fields couple to the states of different chiralities with opposite signs. In an acoustic Weyl system, the implementation of such fields induces chiral Landau levels, which is now observed experimentally.

8 Proton superfluidity and charge radii in proton-rich calcium isotopes 2019-02-12             

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Proton superfluidity and charge radii in proton-rich calcium isotopes

Proton superfluidity and charge radii in proton-rich calcium isotopes, Published online: 11 February 2019; doi:10.1038/s41567-019-0416-9

Spectral study on 36,37,38Ca isotopes and calculations based on density functional theory reveal the interplay between charge radii and nucleonic pairing correlations.

9 Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel 2019-02-09             

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Transient receptor potential melastatin member 8 (TRPM8) is a Ca2+-permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP2), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo-electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP2, and Ca2+ and in complex with the menthol analog WS-12 and PIP2. Our structures reveal the binding sites for cooling agonists and PIP2 in TRPM8. Notably, PIP2 binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2 and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

10 Structural basis of {alpha}-scorpion toxin action on Nav channels 2019-02-09             

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Fast inactivation of voltage-gated sodium (Nav) channels is essential for electrical signaling but its mechanism remains poorly understood. Here, we determined the structures of a eukaryotic Nav channel alone and in complex with a lethal α-scorpion toxin, AaH2, by electron microscopy, both at 3.5-A resolution. AaH2 wedges into voltage-sensor domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular C-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-Å translation to unlatch the intracellular fast inactivation gating machinery. Highlighting the polypharmacology of α-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore-glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Nav channels.

 
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