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Serial crystallography was developed for protein crystal data collection with X-ray free-electron lasers. Here the authors present several examples which show that serial crystallography using high-viscosity injectors can also be routinely employed for room-temperature data collection at synchrotrons.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

PTEN is a key cell signaling lipid phosphatase that is regulated by C-terminal phosphorylation. Biophysical methods were used to illuminate the structural basis for PTEN regulation, which involves a dynamic N-terminal helix that influences catalysis.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

Time resolved serial X-ray crystallography reveals light-driven structural changes in sensory rhodopsin II. These observations explain why this light receptor has a long-lived signaling conformation.

In operando three-dimensional X-ray imaging of a 1T-TaS₂ cryomemory device reveals van der Waals layer restacking, resulting in a bulk metallic switching region, driven by charge rearrangement and concomitant lattice strain.

In this work, Beyer and colleagues have utilized display screening technologies to comprehensively chart RAS proteins “druggability” and in doing so unravel a targetable ligand-induced pocket in RAS opening unprecedented anti-RAS targeted opportunities.

Mussels produce a dynamic bio-interface between their living tissue and their non-living byssus attachment, relevant for design of implant devices. Here, authors discover a mechanoresponsive protein that may mediate mechanosensing at the interface.

The authors in this work apply room-temperature serial X-ray crystallography to fragment screening. This reveals distinct protein conformations and altered binding modes when compared to conventional cryogenic methods, whilst providing similar resolution.

CaMKII is a key enzyme in brain, heart, and egg cells, regulated by calcium signals. Here, authors show that charged residues in the variable linker tune CaMKII activity, a mechanism that may underlie cell type–specific responses.

Using HDX-MS, X-ray crystallography, cryo-EM, and MD simulations, the authors examined the conformational dynamics of GAD65 in its apo- and holo- states and its interaction with the autoimmune polyendocrine syndrome type 2-associated autoantibody b96.11.

The SARS-CoV-2 3CL main protease (3CL M^pro) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL M^pro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.

AlfC transfucosidase is used to modulate fucosylation of glycans decorating monoclonal antibodies. Herein, structural and biophysical characterization reveals the enzymatic mechanism of AlfC and a blueprint for the design of AlfC mutants with novel specificities and functions.

The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the Drosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.

A protein platform rapidly develops peptide-focused major histocompatibility complex class I binders with high specificity.

Here, Rouet et al. present a strategy for the identification of broadly neutralising antibodies against SARS-CoV-2 receptor binding domain from peripheral blood mononuclear cells of convalescent patients, which enabled the identification of a new class 6 epitope.

The photosystem I light-harvesting complex from the salt-tolerant green alga Dunaliella salina has a core configuration composed of only seven subunits. This unusual molecular organization could inform the reconstruction of photosystem evolution.

Glycopeptide antibiotics (GPAs) are microbial natural products synthesized by multiple enzymes, including a nonribosomal peptide synthetase for assembly of the peptide core. Here, the authors use computational techniques to infer a gene set for biosynthesis of an ancestral GPA, produce the peptide in a microbial host, and provide insights into the evolution of key enzymatic domains.

The third variable (V3) loop on the HIV-1 Env glycoprotein is required for viral entry. Here, the authors applied DARPin technology to produce broadly neutralizing inhibitors targeting a region of V3 that becomes accessible after binding to the CD4 receptor.

CD4⁺ T cells recognising shared susceptibility epitope (SE) encoded HLA-DRB1 presenting citrullinated self-peptides are implicated in rheumatoid arthritis. Here the authors characterise the T cell receptor repertoire and structure during recognition of different citrullinated self-epitopes in HLA-DR4 transgenic mice and ACPA + RA patients.

Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.

The infrared view of JWST has opened up the early Universe to study. This Perspective summarizes the key developments in our understanding of the high-redshift Universe from the first 18 months of JWST observations.

There is a growing need for sustainable and green solvent processing of organic optoelectronics. Now Corzo et al. show that terpene solvents in a binary formulation enable device performance on par with that of more toxic solvents.

Three covalent hybrid inhibitors of SARS-CoV-2 main protease (Mpro) have been designed and compared to Pfizer’s nirmatrelvir (PF-07321332), providing atomic and thermodynamic details of their binding to the enzyme, and antiviral potency.

New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.

This study reports the X-ray structure of the α_1B-adrenergic G protein-coupled receptor bound to an inverse agonist, and unveils key determinants of subtype-selective ligand binding that may help the design of aminergic drugs with fewer side-effects.

Nuclear translocation of the p50/p65 heterodimer is essential for NF-κB signaling. Here, the authors identify a bipartite Nuclear Localization Signal in the NF-κB p50/p65 heterodimer that is recognized with high affinity by importin α3.

Canon et al. offer insights into the auto-inhibition and activation of the minus-end directed motor myosin VI. The work highlights how differential relief of auto-inhibition allows for fine control of myosin VI activity in vivo.

Four crystal structures of the human serotonin receptor 5-HT_2BR in complex with chemically and pharmacologically diverse drugs elucidate the structural bases for receptor activation, agonist-mediated biased signaling and β-arrestin2 translocation.

The leading cause of cystic fibrosis is the deletion of phenylalanine 508 (F508del) in the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR). Here authors we develop nanobodies targeting NBD1 of human CFTR and demonstrate their ability to stabilize both isolated NBD1 and full-length protein.

Rossjohn, van der Vliet and colleagues develop single-domain antibodies binding composite CD1d and NKT T-cell receptor antigens, inducing specific antitumor immune subsets.

A crystal structure of the GPCR target of endocannabinoid signaling lipids and drugs, CB1, bound to a negative allosteric modulator (NAM) and an agonist, shows that the NAM binds to a membrane-embedded site reminiscent of the binding site of cholesterol.

Here, the authors show the amyloid formation of a low-complexity domain of NCAP, and its potential for guiding the design of antiviral agents.

The practical use of all-solid-state batteries is hindered by lithium dendrites formed at current densities lower than the threshold suggested by industry research. Here, the authors propose a MHz-pulse-current protocol to circumvent the low-current cell failure and provide mechanistic analyses.

The J-integral is used to quantify resistance to crack propagation. Here, a detailed quantification of the J-integral is demonstrated for a high entropy alloy, by measuring the nanoscale strain and stress fields around crack tips via in situ testing and X-ray nanodiffraction.

Structural and smFRET analysis reveals the mechanism of opposing catalytic activities of bifunctional Rel enzymes; that is, activation of one of the catalytic domains leads to allosteric inactivation of the other.

Recent studies revealed that G protein-coupled receptors rapidly interconvert between multiple states. Here, authors use the kappa opioid receptor (KOR) and show how two state-dependent nanobodies provide real-time reporting of ligand stabilized states with KOR and other GPCRs.

The structure of vanadium nitrogenase reveals key differences from its counterpart molybdenum nitrogenase, particularly in the way it ligands its FeV cofactor, that help to explain the basis for the unique properties of these two nitrogenases.

The authors report a 2.6 Å resolution crystal structure of the human CB1 cannabinoid receptor trapped in the inactive conformation and bound to the antagonist taranabant.

The interaction between the polyelectrolytic IDP ProTα and a highly charged folded protein domain is investigated by integrating NMR, single-molecule FRET and MD simulations. Net charge and charge distribution are implicated in binding and selectivity.

Investigation of the autoproccessing mechanism of SARS-CoV-2 main protease precursors reveals an N-terminal intramolecular cleavage event that leads to increased dimer formation and is followed by an intermolecular cleavage step at the C-terminus.

Structural characterization and catalytic activity of SARS-CoV-2 main protease reveal minimal interface regions enabling dimer formation driven by inhibitor-induced conformational changes of the oxyanion loop.

Mutations in RAS and PI3Kα drive cancer by activating the PI3K-AKT-mTOR pathway. The authors present RAS-PI3Kα structures, revealing interaction interfaces, isoform-specific differences, and a framework for designing PI3Kα-specific inhibitors.

Preclinical studies have shown that blockade of the CD73-adenosinergic pathway could improve anti-tumor immunity and response to other immune checkpoint inhibitors. Here the authors report the results of a randomized phase II trial of first-line durvalumab, paclitaxel and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced triple-negative breast cancer.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials