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Cryogenic electron microscopy structures and functional analyses reveal that NCLX functions as a H⁺/Ca²⁺ rather than a Na⁺/Ca²⁺ exchanger, and uncover its transport mechanism with implications for therapies treating cardiac and neurodegenerative disorders related to abnormal mitochondrial Ca²⁺.

The results of the Fifth RNA-Puzzles contest highlights advances in RNA three-dimensional structure prediction and uncovers new insights into RNA folding and structure.

A peripherally restricted CB1 agonist (VIP36) targeting a cryptic receptor pocket was developed, showing high efficacy in mouse pain models with minimal side effects and tolerance, potentially revolutionizing chronic pain treatment and GPCR drug design.

Ligands that activate GPCRs generally do so by stabilizing a particular conformation of the transmembrane helices. Here, the authors reveal a distinct activation mechanism where a ligand instead stabilizes a particular intracellular loop conformation.

Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

The use of atomic-level simulations reveals a molecular mechanism by which a ligand can achieve selectivity between nearly identical receptors, enabling the rational design of targeted drugs.

The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

Cryo-EM structures of µ-opioid receptor complexes with two agonists coupled to molecular dynamics simulations and functional assays highlight distinct efficacy for G protein subtype activation and β-arrestin recruitment.

Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.

D2 dopamine receptor ligands biased for b-arrestin recruitment were developed based on a receptor homology model that identified conserved ligand contacts within the TM5 and EL2 regions as important for biased signaling.

The authors present structures of FFA2 bound to TUG-1375/4-CMTB or GLPG0974, revealing how the receptor selects lipid chain lengths and is allosterically regulated by synthetic ligands.

Structural findings define the architecture of the mitochondrial pyruvate carrier, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states, providing the molecular basis for understanding its function and inhibition.

Determination of the cryo-EM structures of active neurokinin-1 receptor bound to substance P or the G_q biased peptide SP6–11 reveals that interactions with the receptor extracellular loops regulate G protein signaling selectivity.

Binding modes and molecular mechanisms of several allosteric modulators of a prototypical G-protein-coupled receptor are revealed using atomic-level simulations and validated by the rational design of a modulator with substantially altered effects.

This manuscript describes the structure of an endocannabinoid analog-bound CB1 complex and reveals the structural determinants of ligand efficacy. The activation mechanism, unique to CB1, that is exploited by allosteric modulators is also outlined.

Cryo-electron microscopy structures of the thyrotropin receptor reveal the basis for the activation of the receptor by autoantibodies in patients with Graves’ disease.

A comprehensive spatial expression atlas of the adult human proximal small intestine reveals branched villi, immune activation at the villus tip, and a switch of migrating enterocytes from lipid droplet assembly and iron uptake at the villus bottom to chylomicron biosynthesis and iron release at the tip.

Cryo-electron microscopy structures of human neurotensin receptor 1 in complex with G_i1 protein and the agonist JMV449 reveal a non-canonical state that may represent an intermediate form in G-protein activation.

It is unknown how GPR161, an orphan receptor involved in Hedgehog signaling, is activated. This study identifies a sterol that promotes GPR161-driven cAMP signaling but shows that cAMP is dispensable for Hedgehog pathway repression.

Cryo-electron microscopy structures of the sodium–glucose cotransporter SGLT1 and a related transporter SMCT1 define the architecture of this protein family and provide insights into substrate binding and transport function.

The crystal structure of anion channelrhodopsin-1 (ACR1) from the algae Guillardia theta provides insights into the basis of anion conductance.

Constrained catecholamines gain β₂AR selectivity. Although the orthosteric pockets are identical in β₁AR and β₂AR, surrounding residues allosterically modify the pockets and contribute to the β₂AR selectivity of the constrained catecholamines.

A cryo-electron structure of the µ-opioid receptor in complex with the peptide agonist DAMGO and the inhibitory G protein G_i reveals structural determinants of its G protein-binding specificity.

The ASAP4 family of genetically encoded voltage indicators allows recording of action potentials and subthreshold activity with either one- or two-photon microscopy over extended periods of time.

X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation.

Crystal structures and molecular simulations of the designed anion-conducting channelrhodopsin iC++ provide molecular insights that enable structure-based design of channelrhodopsins with desirable properties for use as optogenetic tools.

The chemokine CXCL10 is associated with pathogenesis of cerebral malaria in Plasmodium falciparum infection. Here the authors show that P. falciparum produces extracellular vesicles laden with RNAs that are taken up by monocytes resulting in a RIG-I and HUR-1 mediated mechanism of inhibition of CXCL10 protein translation.

The cryo-electron microscopy structure of mouse MFSD2A sheds light on the mechanism that underlies its lipid transport functions, which have a pivotal role in regulating the blood–brain barrier.

Transient engagement of the G protein-coupled receptor core can act as a catalyst to activate cellular β-arrestin function after dissociation from the receptor.

Crystal structures of human σ1 receptor bound to the antagonists haloperidol and NE-100, and to agonist (+)-pentazocine, alongside MD simulations, reveal a unique binding pose for, and major conformational rearrangements induced by, the agonist.

The X-ray crystal structure of the human G-protein-coupled receptor protease-activated receptor 1 (PAR1) bound to the antagonist vorapaxar is solved, revealing an unusual method of drug binding that should facilitate the development of improved PAR1-selective antagonists.

The active-state structure of a GPCR occupied by a partial agonist, β₂AR with salmeterol, together with mutagenesis and biophysical studies, explains this ligand's unusual pharmacological profile.

Structures of the iron transporter ferroportin and the peptide hormone hepcidin suggest how iron homeostasis is tightly regulated.

The cryo-EM structure of the zebrafish cation–chloride cotransporter NKCC1 reveals the domain organization, ion translocation pathway, ion-binding sites and key residues for binding activity, providing insights into the activity of this family of transporter proteins with key roles in physiology.

Molecular dynamics simulations and site-directed fluorescence spectroscopy show that the transmembrane core and cytoplasmic tail of G-protein-coupled receptors independently and cooperatively activate arrestin.

The crystal structure of active mouse SMO in complex with the SAG21k agonist and a stabilizing intracellular binding nanobody reveals the structural basis of SMO regulation by PTCH1.

The authors report the crystal structure of the β₂ adrenergic receptor in complex with compound 15, an allosteric modulator that binds to an alternative binding pocket.

The X-ray crystal structure of the M3 muscarinic acetylcholine receptor bound to the bronchodilator drug tiotropium is reported; comparison of this structure with that of the M2 muscarinic acetylcholine receptor reveals key differences that could potentially be exploited to develop subtype-selective drugs.

The X-ray crystal structure of the human β₂ adrenergic receptor, a G-protein-coupled receptor (GPCR), covalently bound to a small-molecule agonist is solved. Comparison of this structure with structures of this GPCR in an inactive state and in an antibody-stabilized active state reveals how binding events at both the extracellular and intracellular surfaces stabilize the active conformation of the receptor. Molecular dynamics simulations suggest that the agonist-bound active state spontaneously relaxes to an inactive-like state in the absence of a G protein.