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Here, the authors determine the cryo-EM structures of chicken ROS1, the ROS1/NEL complex, and the ROS1/NEL/NICOL complex, providing structural insight into how vertebrate ROS1 is activated by the NEL/NICOL ligand–co-ligand complex.

Phosphatidylinositol phosphates together with cholesterol bind at the interface between STING dimers, directly promoting high-order oligomerization.

Phosphatidylinositol 3,5-bisphosphate is a ligand of STING and, together with cGAMP, induces STING activation and innate immune responses.

Authors present cryo-EM structures of the complex of IL-17RA, IL-17RB and ACT1, showing that the IL-17RA and IL-17RB SEFIR domains form an asymmetric hetero-tetramer. These findings provide insights into signalosome formation and immune signaling.

Embedded within the complexity of biological systems lies a formidable task: deciphering the intricate architecture of macromolecules. In this Viewpoint, a panel of experts discuss the key challenges and opportunities of macromolecular structure determination, highlighting the crucial synergy between empirical experimentation and artificial intelligence-based techniques in unravelling these complexities.

Drosophila has a single insulin/IGF receptor (dmIR) that responds to various s insulin-like peptides (DILP ligands). Here, authors determined the cryo-EM structures of dmIR bound with three different DILP ligands and revealed how distinct ligands fine-tune dmIR signaling.

Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective cation channel, in the apo and ATP-bound states.

Using electron cryomicroscopy, the structure of the closed-state rabbit ryanodine receptor RyR1 in complex with its modulator FKBP12 is solved at 3.8 Å; in addition to determining structural details of the ion-conducting channel domain, three previously uncharacterized domains help to reveal a molecular scaffold that allows long-range allosteric regulation of channel activities.

A cell-based phenotypic screen led to the discovery of compounds called NVS-STGs, which bind to the N-terminal domain of STING and act as a molecular glue to induce higher-order oligomerization and activation.

Song et al. developed a computational tool to profile binding pairs between tumor-derived antigens and antibodies from high-throughput B cell receptor sequencing data, predicting response to immune-checkpoint inhibitor therapy and risk of adverse events.

The atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy.

The three-dimensional structure of intact human γ-secretase complex at 4.5 Å resolution is revealed by cryo-electron-microscopy single-particle analysis; the complex comprises a horseshoe-shaped transmembrane domain containing 19 transmembrane segments, and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the horseshoe.

Cryo-EM reveals one mechanism of action of the antimalarial mefloquine: mefloquine binds to the Plasmodium falciparum 80S ribosome, inhibiting protein synthesis in the parasite.

The cryo-electron microscopy structure of human STING bound to both cyclic GMP-AMP and the small-molecule agonist C53 reveals an agonist-binding site in the STING transmembrane domain, and provides insight into the oligomerization and activation of STING.

The genome sequences of 175 Ebola virus from five districts in Sierra Leone, collected during September–November 2014, show that the rate of virus evolution seems to be similar to that observed during previous outbreaks and that the genetic diversity of the virus has increased substantially, with the emergence of several novel lineages.

Through cryo-EM analysis, here authors reveal conformational rearrangements that are critical for the gating mechanism of the human alpha3 Na+/K+−ATPase

The authors solve cryo-EM structures of the alkaline pH-induced insulin receptor-related receptor (IRR), providing clues into its activation mechanism by pH.

Secreted class 3 semaphorins (Sema3s) form tripartite complexes with a plexin receptor and neuropilin co-receptor to transduce signals for neuronal axon guidance and other processes. Here, the authors present the cryo-EM structure of the extracellular Sema3A/PlexinA4/Neuropilin1 complex that provides further insights into the interactions among semaphorin, plexin and neuropilin and reveals long flexible linkers in semaphorin and neuropilin that are important for complex formation.

Activation of c-MET receptor tyrosine kinase involves hepatocyte growth factor (HGF) and glycosaminoglycans, but the molecular mechanism is still under debate. Here, the authors present cryoEM structures of c-MET bound to two HGF splice variants and heparin, revealing the structural basis for c-MET activation.

IGF2 has a distinct binding affinity for two insulin receptor (IR) isoforms and mimics insulin’s function. Here, the authors present the activation mechanism of IR by IGF2 and reveal the molecular basis for IGF2’s different affinity for two IR isoforms.

A cryo-electron microscopy structure of fungal mitochondrial calcium uniporter shows that the channel is tetrameric and sheds light on channel assembly and function.

Plexins are the receptors for the guidance molecules semaphorins and regulate immunity and the development of the nervous and cardiovascular systems. Here authors present a structure of full-length human PlexinC1 in complex with its ligand A39R, which reveals how inter-domain interactions couple extracellular ligand binding to receptor activation and signaling.

A cryo-EM structure of the striatin-interacting phosphatase and kinase (STRIPAK) complex reveals the overall architecture of this large, multisubunit assembly that broadly regulates different signaling pathways.

The activation mechanism of type 1 insulin-like growth factor receptor (IGF1R) is not fully understood. Here, the authors determine the cryo-EM structure of full-length, IGF1-bound IGF1R in the active conformation, providing insights into how IGF1 triggers receptor activation.

Through structural and functional analyses, this work defines the molecular mechanisms underlying the activation of the insulin receptor (IR) involving multisite insulin binding, paving the way for the eventual therapeutic intervention for diseases caused by aberrant activation of IR.

The structure of the D2 dopamine receptor in complex with its G protein reveals how dopamine receptors are activated and, importantly, how a G-protein-coupled receptor can interact with its G protein in a phospholipid membrane.

Genetic mutations of insulin receptor (IR) cause severe insulin resistance syndromes with no current treatment or cure. Here, the authors present that insulin-independent IR activation mechanism by peptide agonist which activate non-functional IR mutants that cause the insulin resistance syndromes.

Cryo-EM analyses provide a near-atomic view of the C. elegans securin–separase complex, with insights into the mechanism by which securin inhibits separase's protease activity.

Cryo-electron microscopy of the tripartite MacA–MacB–TolC multidrug transporter.

Cryo-EM structures of two late-stage assembly intermediates of the human mitoribosomal large subunit reveal the timing of rRNA folding and protein incorporation during the final steps of ribosomal maturation and identify two new assembly factors.

The 20S particle, which is composed of NSF, SNAP and the SNARE complex, is important in fusion events. Single-particle cryo-EM and negative stain EM studies of the 20S particle and of NSF in its different nucleotide states suggest how nucleotide-dependent conformational changes in NSF may generate a force via ATP hydrolysis, providing insight into disassembly of SNARE by NSF.

A 3.7 Å resolution structure for the yeast U4/U6.U5 tri-snRNP, a complex involved in splicing, allows a better appreciation of the architecture of the tri-snRNP, and offers new functional insights into the activation of the spliceosome and the assembly of the catalytic core.

This study determines the structure of the spliceosomal tri-snRNP complex (containing three small nuclear RNAs and more than 30 proteins) by single-particle cryo-electron microscopy; the resolution is sufficient to discern the organization of RNA and protein components involved in spliceosome activation, exon alignment and catalysis.

The cryo-electron microscopy structure of human TBK1 in complex with cyclic GMP–AMP-bound chicken STING reveals a binding mode that suggests that STING phosphorylation by TBK1 requires oligomerization of both proteins.

Cryo-electron microscopy structures of full-length STING show that cyclic GMP–AMP induces a half-turn rotation of the ligand-binding domain relative to the transmembrane domain, forming a tetramer and higher-order oligomers for signalling.

The structure of mouse transient receptor potential mucolipin 1 (TRPML1), a cation channel located within endosomal and lysosomal membranes, is resolved using single-particle electron cryo-microscopy.

Structures of the voltage-gated and phosphatidylinositol 3,5-bisphosphate-activated mouse two-pore channel TPC1 in apo and ligand-bound states provide insights into the selectivity and gating mechanisms of mammalian two-pore channels.

Insulin and insulin-like growth factor (IGF) signalling regulates metabolism, cell growth and proliferation and diverse cell-specific processes. This Review discusses recent structural insights into insulin–receptor and IGF–receptor binding and activation, regulation of insulin and IGF signalling and new agonists with therapeutic potential.

The cryo-electron microscopy structure of a yeast spliceosome stalled before mature RNA formation provides insight into the mechanism of exon ligation.