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Using next-generation cryo-EM and mass spectrometry, we identified 235 chemical modifications in the sub-2 Å resolution structure of the full human 80S ribosome. The newly identified rRNA modifications were found to create new hydrogen bond patterns for riboses and uridines. Ion visualization revealed that Mg2+-associated water molecules are variably substituted by side chains. This study provides the molecular basis for the stabilization of A–U or A–Ψ base pairs and RNA–protein interactions.
The cryo-EM structure of the full 80S human ribosome is presented at 1.9 Å resolution. Numerous new chemical modifications are resolved, resulting in over 230 annotated sites cross-validated by mass spectometry. Ions and water molecules are seen to stabilize the RNA architecture.
Using naive human embryonic stem cells as a model for early embryogenesis, the authors report that the XIST (X-inactive specific transcript) long noncoding RNA recruits repressive histone marks and attenuates X chromosome expression before the establishment of X chromosome inactivation.
Here the authors elucidate how epigenetic regulation influences the regulatory impact of transposable elements in the human genome using cellular models of the neurodegenerative disease XDP, which is caused by an SVA insertion at the TAF1 locus.
Using cryo-electron microscopy, the authors reveal the mechanism by which perampanel-like molecules inhibit AMPA receptors. They show that the inhibitors decouple the ligand-binding domain from the ion channel after neurotransmitter binding and outcompete positive modulators.
Autophagy degrades cellular waste by engulfing it in phagophore membranes and delivering it to lysosomes for degradation. Here Mohan and colleagues identified a type of membrane coat that assembles on phagophores to guide their expansion.
Cryo-electron microscopy (cryo-EM) imaging of DNA replication origin activation explains the role of Mcm10, a minichromosome maintenance (MCM) protein homolog, during initiation. Mcm10 acts as a wedge to split the two MCM hexamers of the activated replicative helicase. Diverging replication forks are then established, with changes in the MCM hexamers that promote the topological separation of two DNA strands.
Macromolecules are involved in myriads of interactions that regulate their cellular function. While years of structural biology progress was built by reducing this complexity, a molecular understanding of biological processes requires the characterization of ever larger and more dynamic molecular assemblies. Cryo-electron microscopy is rising to this challenge.
In this Perspective, the authors propose a framework to explain membrane protein biogenesis, wherein different parts of a nascent substrate are triaged between Oxa1 and SecY family members for insertion.
Here, using cryo-EM and biochemistry, the authors delineate how the XPD helicase unorthodoxly uses its Arch domain to separate double-stranded DNA upon approaching a DNA lesion, promoting our understanding of NER bubble formation and damage verification.
The molecular mechanisms that regulate the transition from totipotency into divergent cellular states are unclear. Two new studies show that the transcription factors TFAP2C, NR5A2 and TEAD4 (TNT) support the formation of a transient bipotent state by activating early pluripotency and trophectoderm genes and modulating HIPPO signaling.
Here the authors identify the transcription factors TFAP2C and TEAD4 as a bistable switch that reconciles into Hippo ON and OFF states, establishing a composite state at the eight-cell stage and critically regulating lineage diversification.
The authors solve a cryo-EM structure of the regulatory subunit of human protein phosphatase 2A in complex with HIV-1 Vif-containing E3 ligase, leading to improvement of our understanding of host–virus protein interactions.
The commander complex was recently shown through interactomic screens to be a ubiquitous and conserved protein complex with fundamental biological roles. Two recent reports together revealed the structure of the complete commander assembly and explored its functional implications.
Here the authors show that active DNA demethylation and transcription factor occupation at distal regulatory elements is essential for pluripotency maintenance in dormancy conditions.
Using time-resolved cryo-EM, the authors capture complete structural snapshots of the enzymatic cycle coupled with channel gating in a TRPM-type channel enzyme.
The authors revealed that the general translation factor eIF4A exerts a repressive effect on a subset of mRNAs by enhancing LARP1 and TOP mRNAs during mTORC1 inhibition under stress.
This issue of Nature Structural & Molecular Biology presents studies investigating RNA processing, including mechanisms of splicing, biogenesis of the splicing machinery, decoding of mRNA by the ribosome, and deadenylation of mRNA for degradation. We are also delighted to be publishing News & Views and Comment pieces that reflect on these exciting advances in the field.
NAD(H) redox homeostasis has a fundamental role in cellular metabolism. We screened for potential modulators of NAD(H) using a genome-scale RNA interference (RNAi) approach combined with SoNar, a high-performance sensor that is sensitive to the redox state of NAD(H). Our analysis identified HES4 as a negative regulator of the NADH/NAD+ ratio that influences pyrimidine biosynthesis and exerts a potent oncogenic effect.