Research articles

Cryo-electron microscopy structures of parathyroid hormone receptor 1–β-arrestin complexes reveal key conformational changes, enabling the design of G-protein-biased agonists with selective signaling properties and therapeutic potential.

This work introduces the Runs N’ Poses dataset for benchmarking deep learning methods on the protein–ligand complex prediction task. It shows that current methods rely on memorization, challenging their effectiveness for real-world applications such as drug discovery.

Schöndorf and Petrychenko et al. show that mitochondrial translation speed is coupled to OXA1L-mediated inner membrane insertion, with cotranslational nascent chain folding and insertion driving structural changes and translational pausing.

Singh et al. combine cryo-electron microscopy and functional studies to reveal how a single protein complex selects diverse mRNAs for subcellular localization using a combination of shape, positional sequence information and number of structured RNA elements.

Chromatin dynamics govern search times between DNA elements. Using integrated MINFLUX imaging, Mazzocca, Narducci, Grosse-Holz and colleagues track chromatin dynamics over seven orders of magnitude in time, revealing two dynamics classes and providing bounds on search times.

Wan et al. develop a deep loop profiling to uncover how sequence diversity in the complementarity-determining regions of single-domain antibodies shapes folding fitness, thereby enabling the design of more robust synthetic antibody libraries.

The authors performed computational and experimental analyses to reveal how Smoothened directly inhibits PKA through an intrinsically disordered region, defining a central step in Hedgehog signaling and a mechanism of G-protein-coupled receptor–kinase regulation.

The authors show that MTCH2 promotes BAX and BAK oligomerization independently of its insertase activity, supporting its role in shaping the mitochondrial lipid environment that enables efficient pore expansion, mitochondrial DNA release and inflammatory signaling.

Here, the authors elucidate TMPRSS2 protease recognition of the SARS-CoV-2 spike S₂′ cleavage site, revealing the molecular basis of activation of membrane fusion, and show that antibodies recognizing the S₂′ site or TMPRSS2 block viral entry by interfering with TMPRSS2 access.

Rawal, Kwon and colleaugues obtain cryo-electron microscopy structures and biochemical analyses that reveal how RAD51 paralog exchange remodels distinct complexes with different functions to regulate DNA repair by promoting RAD51 filament formation.

Kim et al. revealed how taste receptor type 2 member 43, a bitter taste receptor that detects coffee-derived compounds, recognizes bitter tastants through cryo-electron microscopy structures of ligand-bound complexes, supported by biochemical and computational analyses, providing a structural framework for coffee bitter taste signaling.

Tan, Yu, Han et al. show how human bitter taste receptors recognize diverse ligands by determining several T2R structures. The study presents distinct binding modes and an intrinsic activation mechanism.

Feng, Alvarenga et al. use cryo-electron microscopy to visualize the activation of the transmembrane protein 16F channel and scramblase in liposomes to show that it adopts a conformation that forms separate pathways for ions and lipids, thereby rationalizing its dual activity.

Guan, Ocampo and colleagues report the discovery and mechanistic dissection of Al3Cas12f, a metagenome-derived miniature nuclease that retains notable genome-editing capacity. They engineer an RKK variant, which boosts editing and helps overcome the potency threshold that has limited compact editors.

Sugar porters are textbook examples of how transport activity is described by Michaelis–Menten kinetics. Here, using saturation transfer difference nuclear magnetic resonance spectroscopy, Ahn et al. conclude that the fully occluded state of a sugar transporter is analogous to the transition state in soluble enzymes.

Zehr et al. revealed the 2.7-Å cryo-electron microscopy reconstruction of human microtubules in situ in the axon of induced pluripotent stem cell (iPS cell)-derived neurons. It shows an expanded microtubule lattice yet bound to GDP, in contrast to the compacted lattice observed at the iPS cell stage.

Burr and Auckland et. al develop MitoPerturb-Seq, which combines single-cell screening with multiomics to link nuclear genes to mitochondrial DNA (mtDNA) dynamics. They unveil core regulators of mtDNA copy number and characterize cell-cycle delays and transcriptional stress in response to mtDNA depletion.

Dutta et al. demonstrate that the tumor suppressor complex BRCA1–BARD1 physically interacts with the RNA–DNA helicase Senataxin (SETX) and upregulates the activity of SETX to resolve harmful R-loops crucial for the avoidance of transcription–replication conflicts.

Liu et al. show that the C9orf72 GGGGCC-repeat RNA drives liquid-to-solid phase transition of poly(GR) in ALS/FTD through forming G-quadruplex and hairpin scaffolds, whereas targeting the RNA structures with small molecules reduces poly(GR) aggregation and cellular dysfunction.

Wang, Guo, Zhang and colleagues obtain four cryo-electron microscopy snapshots that show how IscB is kept off by two RNA lids, with a car-pedal-like guide shift activating cleavage after ~11-nt pairing. They also engineer hinge regions that boost flexibility and improve genome editing in cells.