Volume 30 Issue 7, July 2023

Immunoglobulin M (IgM) is the most ancient antibody class and key mediator of the primary immune response. New structures reveal how it binds to its only class-specific receptor (FcμR) and offer a tantalizing clue to the role of FcμR in the IgM B cell receptor.

A study on a yeast model explores how ssDNA gaps induce cell death and genomic instability, implicating Rad9 and Rad51 in gap repair and protection. Gaps forming secondary structures trigger chromosome fragility, deletions, rearrangements, or cell death pathways, showing how gaps are a vulnerability in cancer cells with opportunity for selective targeting.

Cryo-electron microscopy (EM) structures and molecular dynamics simulations of organic cation transporters (OCTs) in ligand-free and drug-bound states provide insights into drug recognition by OCTs. As OCTs are largely responsible for the hepatic uptake and renal clearance of hundreds of drugs, these results will help to inform future drug design and development efforts.

The activity of genes is controlled by regulatory DNA sequences, which interact and communicate with their target genes over long genomic distances. New analyses show that the Mediator complex contributes to the formation of these long-range interactions in the genome.

In this Review, the authors present and discuss the mechanistic and functional implications of new cryo-EM structures of telomerase from different species, contextualizing the new insights in light of existing functional analyses and decades-long hypotheses and conundrums.

Here, the authors show that anchoring of the PRC2 complex to its own sites requires nuclear condensation of Ccc1, a H3K27me3 reader in the yeast Cryptococcus neoformans, suggesting a functional role for condensates in ensuring heterochromatin fidelity.

Using a combination of biochemical, structural and computational analyses, the authors unveil the mechanism of bacterial RNA polymerase pausing and restart mediated by a small-molecule-dependent RNA structural element termed a riboswitch.

Here, the authors show that the lncRNA LoNA links nucleolar structure to epigenetic reprogramming and zygotic genome activation. Loss of LoNA leads to 2C arrest by impairing nucleolar assembly and repression of 2C gene transcription.

The structure of synapses is critical for brain function. Yu et al. show how the synaptic vesicle protein synaptogyrin binds lipids and helps to ensure that vesicles are uniformly sized, allowing for precise storage of neurotransmitters.

Here, the authors show that chromatin at certain transposable elements (TEs) is coated with acetylation at H4K16, which can lead to increased local chromatin accessibility and transcription activation. In turn, these acetylated TEs display enhancer-like capabilities to regulate gene expression in cis.

The presence of Trim24 increases cell viability upon stress and enables p53 to influence gene expression as a function of the local chromatin state.

Using cryo-electron tomography, Lopez-Robles, Scaramuzza, Astorga-Simon, Ishida et al. solve the architecture of ESCPE-1, a protein scaffold that mediates the recycling of cargo from endosome to trans-Golgi network and plasma membrane in tubular carriers.

Using structural, functional and spectroscopic investigations of a bacterial inward proton-pumping rhodopsin, Kovalev et al. reveal its molecular mechanism and show how proton wires mediate ion selectivity and direct proton transport through cell membrane.

Zhang, Tang, Gao et al. report structural and functional properties of the Omicron BA.2 spike protein, and replication kinetics of the virus. Their results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility.

Here, the authors map chromatin conformation at high resolution after rapid Mediator depletion to show that its loss reduces the frequency of enhancer-promoter interactions and associated gene expression, with a corresponding redistribution of Cohesin.

Organic cation transporters (OCTs) are responsible for the hepatic uptake and renal clearance of well over 250 US Food and Drug Administration-approved drugs. Suo et al. solved cryo-electron microscopy structures of OCT variants in complex with xenobiotics, providing insights into drug recognition by OCTs.

Zhu et al. report four cryogenic electron microscopy structures of γ-aminobutyric acid transporter 1 at 2.2–3.2 Å in inward-occluded or inward-open conformations, and elucidate the molecular basis for γ-aminobutyric acid recognition and mode of action of two inhibitors, nipecotic acid and tiagabine.

The GABA transporters (GATs) enforce spatiotemporal control of the inhibitory neurotransmitter GABA at neural synapses. Nayak et al. report the structure of substrate-bound GAT1 in an ion-bound cytosol-facing conformation, providing mechanistic insights into GABA selection and reuptake.

Cryogenic electron microscopy analysis of a complex between the immunoglobulin M (IgM) pentamer and the IgM-specific Fc receptor shows how the receptor specifically recognizes the constant regions of polymeric serum IgM or the membrane-associated B-cell receptor.

Here, using plasmonic DNA origami nanorotors, the authors observe in real time the R-loop formation and locking by the clustered regularly interspaced short palindromic repeats–Cas surveillance complex Cascade, thus reconstructing the underlying energy landscape and dynamics of this process.