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The conformational preference of the selectivity filter in KcsA shifts with the intracellular activation gate changing from partially to fully open. The x axis describes the width of the selectivity filter and is defined as the average cross-subunit pinching distance between the Cα atoms of Gly77. The y axis indicates the potential of mean force along the x axis. The upper and lower plots represent partially and fully open intracellular activation gate, respectively. The typical conformations for the free energy basins are shown in stick and ribbon for protein and van der Waals representation for both water and K+ ions. The wireframe represents the density of water molecule in the crystal structures (PDB ID 1K4C or 1K4D). See page 1408.
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Predicting voltage sensing
New method predicts the molecular basis of membrane proteins’ voltage sensitivity.
Influences: Experimenting with multidisciplinary training
Cheng recalls the multidisciplinary influence of his trans-Pacific training.
The exquisitely cooperative nature of Orai1 channel activation
Yeung and Prakriya highlight new research showing that STIM1 must bind to all six Orai1 subunits to effectively activate the channel.
Opening leads to closing: Allosteric crosstalk between the activation and inactivation gates in KcsA
Delemotte appraises new computational work revealing that the intracellular activation gate must open for C-type inactivation to occur in K+ channels.
Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors
Burger et al. summarize our mechanistic understanding of allostery in the prototypical GPCR, the muscarinic acetylcholine receptor.
Physiological CRAC channel activation and pore properties require STIM1 binding to all six Orai1 subunits
The quantitative relation between STIM1 binding to Orai1 and store-operated CRAC channel activation is not well understood. Yen and Lewis find that STIM1 must bind to all six Orai1 subunits to effectively open the channel and generate the high ion selectivity and low conductance seen in native cells.
Phenotypic plasticity in Periplaneta americana photoreceptors
Neuronal plasticity in adulthood is important for adaptation to different environments. Frolov et al. show that rearing mature Periplaneta americana in prolonged light or dark leads to distinct changes in photoreceptor responses, suggesting remodeling of the light-sensitive membrane.
Determinants of selective ion permeation in the epithelial Na+ channel
The origin of ion selectivity in epithelial Na+ channels and the closely related acid-sensing ion channels is uncertain. Yang and Palmer show that the site of ion selectivity in epithelial Na+ channels is more extracellular than that proposed for acid-sensing ion channels.
Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel
C-type inactivation in K+ channels is thought to be a result of constriction of the selectivity filter. By using MD simulations, Li et al. show that rapid constriction occurs within 1–2 s when the intracellular activation gate is fully open, but not when the gate is closed or partially open.
One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels
Retigabine is a widely studied potassium channel activator that is thought to interact with a conserved Trp side chain in the pore domain of Kv7 subunits. Yau et al. demonstrate that drug sensitivity in just one of the four subunits is sufficient for a near-maximal response to retigabine.
Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener
Kv7 potassium channels are strongly activated by a variety of small molecules with diverse mechanisms of action. Wang et al. investigate a compound that targets the voltage-sensing domain, ICA-069673, and demonstrate that four drug-sensitive subunits are required for maximal effect.
Determining the molecular basis of voltage sensitivity in membrane proteins
The identification of voltage-sensing elements in membrane proteins is challenging due to the diversity of voltage-sensing mechanisms. Kasimova et al. present a computational approach to predict the elements involved in voltage sensing, which they validate using voltage-gated ion channels.