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Glycine receptors (GlyR) are a critical postsynaptic component of spinal neurons. Here, the auhtors present cryo-EM structures of a heteromeric GlyR in the presence of an antagonist, agonist and agonist with a positive allosteric modulator.

Drugs with partial activity at the serotonin 3 receptors (5-HT₃R) are suited to normalize serotonin response in treating irritable bowel syndrome. Felt et al. demonstrate the mechanism of partial agonism in 5-HT_3AR using cryo-EM.

Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Here, authors present cryo-EM structures of the full-length glycine receptors (GlyRs) reconstituted into lipid nanodiscs in the unliganded, glycine-bound and allosteric modulator-bound conformations and reveal global conformational changes underlying GlyR channel gating and modulation.

Serotonin receptors (5-HT₃R) belong to the pentameric ligand-gated ion channel superfamily and mediate excitatory postsynaptic signaling. Here the authors present the high-resolution cryo-EM structure of 5-HT_3AR bound with the competitive antagonist granisetron and further validate the granisetron-binding mode with electrophysiology measurements and MD simulations.

Glycine receptors (GlyRs) mediate motor control and pain perception. Here, Kumar et al. present structures of GlyR bound to Δ9 -tetrahydrocannabinol (THC) using cryo-electron microscopy, providing insight into the therapeutic effects of cannabinoids.

Serotonin receptor (5-HT_3AR), a pentameric ligand-gated ion channel, regulates numerous gastrointestinal functions. Here the authors provide a cryo-electron microscopic structure from the full-length 5-HT_3AR in the apo-state which corresponds to a resting conformation of the channel.

The K+ channels can display three distinct gating modes. The molecular basis for two of these modes (low open probability and flickery) are now examined by a combination of single-channel recording, crystallography and modeling of mutants in Glu71, revealing that changes in ion and water occupancy in and around the selectivity filter determine modal gating.

A series of long molecular dynamics simulations shows that the K⁺ channel is sterically locked in the inactive conformation by buried water molecules bound behind the selectivity filter; a kinetic model deduced from the simulations shows how releasing the buried waters can elongate the timescale of the recovery period, and this hypothesis is confirmed using ‘wet’ biophysical experiments.

Recent structural and functional analyses of MthK, a prokaryotic Ca²⁺-activated K⁺ channel, suggest that the interplay between cytoplasmic Ca²⁺ and H⁺ concentrations determines the oligomeric stability of its associated RCK domain and thus controls activation gating. However, the discovery of a ligand-dependent desensitization process suggests that gating in these channels might be more complicated than originally envisioned.

Cryo-electron microscopy structures of the serotonin-bound 5-HT_3A serotonin receptor show the receptor populating two distinct states, characterized by twisting in the extracellular and transmembrane domains relative to the apo state, which creates pathways for ion permeation.

Mitochondria defects caused by mutant huntingtin (mtHtt) have been implicated in Huntington's disease. Here authors show that VCP binds to mtHtt on the mitochondria, and that treatment with a peptide that disrupts this interaction reduces the cellular and behavioural deficits in mouse models of HD.

The cryo-EM structure of the full-length TRPV5 channel in complex with inhibitor econazole reveals a domain-swapped architecture and provides insights into mechanisms of inhibition.

K⁺ channels can convert between conductive and non-conductive forms through mechanisms that range from flicker transitions (which occur in microseconds) to C-type inactivation (which occurs on millisecond to second timescales). Here, the mechanisms are revealed through which movements of the inner gate of the K⁺ channel KcsA trigger conformational changes at the selectivity filter, leading to the non-conductive C-type inactivated state.