Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs.

Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered.

Molecular mechanism of setron-mediated inhibition of full-length 5-HT receptor.

Serotonin receptor (5-HTR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HTR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HTR are not fully understood.

Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT receptor.

The 5-HT serotonin receptor, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies. Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT receptor in distinct conformations at 3.

Cryo-EM structure of 5-HT receptor in its resting conformation.

Serotonin receptors (5-HTR) directly regulate gut movement, and drugs that inhibit 5-HTR function are used to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. The 5-HTR function involves a finely tuned orchestration of three domain movements that include the ligand-binding domain, the pore domain, and the intracellular domain. Here, we present the structure from the full-length 5-HTR channel in the apo-state determined by single-particle cryo-electron microscopy at a nominal resolution of 4.

Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel.

Desensitization in pentameric ligand-gated ion channels plays an important role in regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω-3 polyunsaturated fatty acid in synaptic membranes, enhances the agonist-induced transition to the desensitized state in the prokaryotic channel GLIC. We determined a 3.

Genetic and molecular characterization reveals a unique nucleobase cation symporter 1 in Arabidopsis.

Locus At5g03555 encodes a nucleobase cation symporter 1 (AtNCS1) in the Arabidopsis genome. Arabidopsis insertion mutants, AtNcs1-1 and AtNcs1-3, were used for in planta toxic nucleobase analog growth studies and radio-labeled nucleobase uptake assays to characterize solute transport specificities. These results correlate with similar growth and uptake studies of AtNCS1 expressed in Saccharomyces cerevisiae.