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Cryogenic electron microscopy structures and functional analyses reveal that NCLX functions as a H⁺/Ca²⁺ rather than a Na⁺/Ca²⁺ exchanger, and uncover its transport mechanism with implications for therapies treating cardiac and neurodegenerative disorders related to abnormal mitochondrial Ca²⁺.

Monoclonal antibodies targeting the conserved neuraminidase catalytic site mimic sialic acid and use coordinated water molecules to inhibit diverse influenza A and B viruses, including H5N1, providing broad prophylactic protection in mice.

Potential ligand class-dependent differences in STING activation have both evolutionary and therapeutic implications. Here, the authors observe a unique oligomerization state of STING with an open-LBD ligand, suggesting additional regulatory mechanisms involved in activation by this ligand class.

GTPase-activating proteins (GAPs) often contain regulatory PH domains. In this work, Soubias et al, using an integrated structure-function approach, discovered a mechanism where a GAP PH domain binds directly to a GTPase to induce allosteric changes facilitating GTP hydrolysis.

Garnet-type LLZO electrolytes are considered among the most promising solid-state electrolytes for all-solid-state batteries; however, numerous challenges need to be addressed before they are integrated into a cell. By precipitating amorphous zirconium oxide onto grain boundaries, increased ionic conductivity is observed and dendrite growth is suppressed.

Geospatial estimates of the prevalence of anemia in women of reproductive age across 82 low-income and middle-income countries reveals considerable heterogeneity and inequality at national and subnational levels, with few countries on track to meet the WHO Global Nutrition Targets by 2030.

Nucleic acid superstructures are required to package genomes into the nucleus of cells. In this study, the superstructure of an RNA supercoil species is reported and is shown to be dependent on an RNA-binding protein that induces a higher level of organization compared with DNA superstructures.

Energy–structure–function maps that describe the possible structures and properties of molecular crystals are developed, and these maps are used to guide the experimental discovery of porous materials with specific functions.

Ptychography computationally reconstructs high-resolution images from overlapping diffraction patterns, recovering both amplitude and phase information. This Primer covers the technique’s principles, diverse wavelength implementations from optical to electron regimes, advanced reconstruction strategies and applications ranging from live cell imaging to atomic-resolution materials characterization.

During a photoinduced phase transition, electronic rearrangements are usually faster than lattice ones. Time-resolved measurements now show that the insulator-to-metal transition in a thin-film Mott insulator is preceded by lattice reconfiguration.

Identifying determinants of broadly neutralizing antibodies against hepatitis C virus (HCV) may guide HCV vaccine design. Here, the authors discover new anti-HCV antibodies using computational screening and analyze the amino acid composition and sequence-structure relationships in this antibody family.

Pertussis toxin is used extensively for perturbing Gαi/o pathways in the study of physiology and disease, but an equivalent inhibitor of Gαq signalling is not currently available to the research community. Here the authors characterize FR900359 as a specific Gq inhibitor and demonstrate its utility to dissect GPCR signalling and its potential to inhibit melanoma cells.

Epidermal growth factor receptors have been shown to oligomerise upon binding to their cognate ligands. Here, the authors use biochemical, biophysical and cell biology techniques to analyse the structures of these oligomers, and argue that these formations are required for signalling.

Imaging live cells at nanometre resolution is challenging because radiation damage kills the cells during exposure. Here, the authors overcome this difficulty in a ‘diffraction before destruction’ experiment using an X-ray laser and record signal to 4 nm resolution on a free-flying cell.

Echinocandins inhibit the biosynthesis of β−1,3-glucan, an essential component of the fungal cell wall, but their efficacy against the pathogen Aspergillus fumigatus is limited. Here, Dickwella Widanage et al. show that A. fumigatus responds to echinocandin treatment by remodelling various cell wall polymers, thus maintaining cell wall integrity and modulating the permeability and circulation of the drug in the cell wall.

A crystal structure of bacterial multidrug transporter LmrP reveals the presence of a lipid inside the substrate binding cavity, with MD simulations and mutational analyses suggesting it could be involved in broad substrate specificity.

Guided by a structure of VGLUT2 with substrate, Li et al. identify the mechanisms for selective substrate recognition, a role for lipid modification in limiting axonal dispersion and for the cytoplasmic gate in allosteric regulation by lumenal H⁺.

It is often assumed that systems that can be analyzed accurately via mean-field theory would not be worth looking at using quantum algorithms, given entanglement plays no key role. Here, the authors show instead that a quantum advantage can be expected for simulating the exact time evolution of such electronic systems.

Identification of specificity from antibody sequence is challenging especially when different clonotype lineages recognise antigens similarly in a process of convergence. Here using TREM2 reactive antibodies in rats as an example the authors characterise convergent antibodies and identify similarities in recognition between different lineages.

MUTYH removes A mis-incorporated opposite oxidized guanine to thwart mutations. Here, the authors present crystal structures and assess functional impacts and molecular dynamics of cancer-linked variants to illuminate how the [4Fe-4S] cofactor and active site are allosterically connected with significance for fidelity and clinical impact.

The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of structure determination from nanocrystals of macromolecules that cannot be grown in large crystals. Over three million diffraction patterns were collected from a stream of nanocrystals of the membrane protein complex photosystem I, which allowed the assembly of a three-dimensional data set for this protein, and proves the concept of this imaging technique.

In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.

An integrated approach combing solution and solid-state NMR, molecular dynamics simulations and neutron reflectometry is applied to characterize dynamic membrane bound forms of ADP-ribosylation factor 1 (Arf1).

The formation of C-C bonds in fatty acid and polyketide biosynthesis depends on β-ketoacyl-acyl carrier protein (ACP) synthases (KSs). Here, the authors present structures of E.coli KSs bound to substrate mimetic bearing ACPs, providing insights into the catalytic mechanism underlying C-C bond forming reactions.

A combination of structural and biochemical analyses of MlaC, the soluble periplasmic component of the Mla pathway, elucidate how this protein assists phospholipid movement between the bacterial inner and outer membranes.

The hexagonal immature capsid lattice of human endogenous retrovirus K is determined at 3.2 Å resolution, which is an assembly of small molecule-stabilized hexamers via dimer and trimer interfaces, a highly conserved mechanism among retroviruses.

Autotransporter proteins are localised to the bacterial surface and promote colonisation of host epithelial surfaces. Here, the authors present the crystal structure of autotransporter UpaB and show evidence for distinct binding sites for glycosaminoglycans and host fibronectin.

Uptake of vitamin B₁₂ is important for colonisation of the gut by Bacteroides species. Here the authors characterise B₁₂ uptake in Bacteroides thetaiotaomicron, mediated by outer membrane protein complexes consisting of surface-exposed BtuG lipoproteins and BtuB TonB-dependent transporters.

The drug Xanomeline is progressing through clinical trials for the treatment of patients with schizophrenia. Here, the authors determine a cryo-EM structure of Xanomeline bound to its primary target revealing a dual binding mode mechanism.

Here the authors use NMR, SAXS and MD simulations to characterise the structure of proteusin peptides, which are atypically long RiPP substrates. They show a small, unstructured region in the proteusin leader is sufficient for its interaction with a halogenase that brominates the terminal tryptophan residue.

Implant-associated infections with Staphylococcus aureus pose serious clinical challenges. Here, the authors develop a biosensor based on toxin-responsive liposomes encapsulating gold nanoclusters, providing a non-invasive, colourimetric diagnostic tool for bacterial infection detection with urinary readout.

In this work, the authors use a centrifuge force microscope for high-throughput single-molecule experiments to elucidate stacking energies between individual bases of DNA.

Common protonophores—previously known as protein-independent proton translocators—activate mitochondrial heat production due to H⁺ leak through the ADP/ATP carrier and uncoupling protein 1.

A 9-nm-resolution structure of PR772 virus and a movie of its continuous conformational changes are determined from single-particle X-ray scattering data.

Flycatcher1 (FLYC1) is a candidate mechanosensitive channel involved in Venus flytrap touch-induced prey capture. Here, the authors report structural and functional details of FLYC1, with insights into gating conformational transitions.

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.

Human enterovirus 71 (EV71) contains an internal ribosome entry site (IRES) that promotes translation of viral RNA. Here the authors show that an antiviral small molecule DMA-135 binds to the EV71 IRES RNA, inducing conformational change and stabilizing a ternary complex to repress translation.

Melting and crystallization of ice close to the triple point is mediated by a thin liquid layer of water. Within an extended theoretical-numerical model, Sibley et al. capture both equilibrium properties and kinetic aspects of the film evolution to arrive at a broader perspective of how ice grows.

Biochemical and structural approaches define how the chaperone TAPBPR interacts with MR1 molecules, including empty and ligand-loaded MR1, and facilitates presentation of metabolite-derived antigen ligands by MR1 complexes.

The viral Protein Kinase-1 (PK-1) phosphorylates the regulatory protein p6.9, which facilitates baculoviral genome release. Here, the authors combine X-ray crystallography with biophysical and biochemical analyses as well as molecular dynamics simulations to characterize Cydia pomenella granulovirus PK-1, which forms a dimer with a parallel side-to-side arrangement of the kinase domains and furthermore, they provide insights into its catalytic mechanism and evolutionary relationships with other kinases.

Computational methods for the de novo design of conformationally restricted peptides produce exceptionally stable short peptides stabilized by backbone cyclization and/or internal disulfide bonds that are promising starting points for a new generation of peptide-based drugs.

The nucleus-like compartment formed in bacteria during infection by jumbo phage 201phi2-1 is composed of the bacteriophage protein chimallin, which can self-assemble into closed compartments in vitro.

Mucosal-associated invariant T (MAIT) cells recognize vitamin B metabolites presented by the molecule MR1. Rossjohn and colleagues generate multiple altered metabolite ligands and determine their structures in the context of MR1 and the TCR to develop a generalized framework for MAIT cell antigen recognition.

The authors report the near-atomic structure of the ex vivo aRML prion fibril. The comparison between this structure and the previously solved 263K prion fibril shows that both common and divergent features characterize these prion strains and their respective conformational replication templates.

Halophilic organisms thrive in high salt conditions and express proteins that display desirable characteristics for industrial applications. Here, the authors use a rational design approach to transform wild-type carbonic anhydrase into a strongly halophilic enzyme.