Research articles

Here, the authors generated and analyzed run-on sequencing data to observe transcription in species across the tree of life to uncover the origins of the promoter-proximal pause.

Zeng et al. applied single-particle cryo-electron microscopy to native samples isolated from the human parasite Toxoplasma gondii, determining multiple structures of key components of the conoid, a cone-shaped organelle essential for host cell invasion.

Here the authors present an artificial-intelligence-based automated method for improved protein structure determination from cryo-EM density maps by efficiently integrating map information and structure prediction.

Riechmann et al. uncover structural features governing ubiquitin transfer from ubiquitin-activating E1 enzymes UBA1 and UBA6 to specific E2 ubiquitin-conjugating enzymes, revealing a hierarchy of E2 activity with cognate E1s.

Mitochondrial translational activators (TAs) facilitate transcript-specific translation. Using selective ribosome profiling and cryo-electron microscopy, the authors show that TAs bind to the 5′ untranslated region of their target transcript to position mitoribosomes for initiation.

Vidmar et al. use cryo-EM to reveal how bacterial RNA polymerase (RNAP) and topoisomerase I (TopoI) cooperate. TopoI switches conformation, senses DNA supercoils near RNAP and relaxes them. Mutations disrupting this process alter bacterial motility and operon polarity.

By reconstituting and visualizing mammalian transcription elongation at the single-molecule level, Wang et al. dissected the effects of individual elongation factors on the speed of RNA polymerase II, which is found to operate as a multi-gear molecular machine.

Rocha-Roa et al. identify TMEM170 proteins as endoplasmic reticulum lipid scramblases that partner with bridge-like lipid transfer proteins BLTP1/Csf1 proteins to enable bulk lipid transport between organelles.

Carty et al. identify the H3K9 methyltransferases that restrict the size and position of the centromere protein A chromatin domain, maintaining functional centromeres.

Mi et al. use de novo protein design to address bystander and off-target editing in base editing, resulting in a highly precise mitochondrial cytosine base editor that is valuable for studying and treating mitochondrial diseases.

Elhan et al. show that ATG2A acts with DGAT2, the enzyme producing triacylglycerol (TAG), in lipid droplet growth. By delivering diacylglycerol to lipid droplets, ATG2A not only fuels TAG production but also promotes the recruitment of DGAT2 to droplet surfaces.

Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that FAM118A/B processing of NAD involves head-to-tail filament formation and a partnership between the two paralogs.

Inspired by the advance in protein structure prediction, CryoAtom builds protein models directly from cryogenic electron microscopy maps, producing more complete models, reducing the resolution requirement and accelerating modeling.

Zhou et al. report cryo-electron microscopy structures of human SLC37A4 in four states, elucidating conformational transitions during glucose-6-phosphate/phosphate transport and S-4048 inhibition. This study links structural mechanisms to glycogen storage disease type Ib pathology, offering therapeutic insights.

Lai and Xu et al. used cryo-electron microscopy and functional analyses to elucidate the glucose-6-phosphate uniport mechanism of human solute carrier family 37 member 2 and its structural dynamics, offering insights into glucose metabolism and related disorders.

AlphaSync synchronizes AlphaFold Protein Structure Database predictions with UniProt sequences, providing up-to-date protein structures with residue-level annotations for humans, model organisms and pathogens through an accessible web interface and application programming interface.

He, Teng and Yang et al. report how metformin, the widely used antidiabetic drug, inhibit its target, the respiratory complex I, through a distinct state-dependent, inhibitor trapping mechanism, thus providing the molecular basis for its superior clinical tolerance.

The authors use time-resolved cryo-electron microscopy to reveal the interactions of the redox-active cofactor TXNL1 with the human 26S proteasome and detect ATPase motor states that indicate burst-like mechanisms for hand-over-hand substrate translocation.

Teng and Zeng et al. use cryo-electron microscopy to show that the crescent scaffold of KICSTOR anchors GATOR1 to lysosomes and disruption of the interaction causes mTORC1 hyperactivation and TFE3 mislocalization. KICSTOR enables nutrient-dependent mTORC1 regulation by binding anionic lipids for lysosomal targeting.

Li et al. further develop a high-throughput peptide-centric local stability assay that speeds up sample preparation 100-fold and extends protein–ligand identification to membrane proteins, tissues and bacteria.