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The antidepressant vortioxetine affects rodent and human 5-HT₃ receptors differently. López-Sánchez et al. use a variety of methods, including structure determination of vortioxetine-bound human and mouse 5-HT₃ receptors, to reveal the basis of these differences.

Enantiopure zeolites are sought for enantioselective catalytic and separation processes. Here, the authors use chiral organic structure directing agents derived from sugars, guiding the crystallization process toward enantiomorphically pure S-STW zeolites.

Wilcox et al. (2022) show that NMDA receptor channel blockers, some of which are clinically important drugs, can access their binding site via 2 routes: a well-known path from the extracellular solution, and another path through the plasma membrane.

Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore.

Here authors aim to understand the 5-HT_2AR coupling signature in response to different signaling probes and their physiological impacts using computational modeling, in vitro and in vivo experiments, and analysis of human brain tissue.

Lin et al. report a mechanism of RHOA GTPase signaling in the context of oncogenic mutations. The results show that RHOA mutants can interact with effectors in the GDP-bound state, and that their structural dynamics are important for activity.

Zhang and colleagues report that multicellular clusters of circulating tumor cells are more resistant to killing by natural killer (NK) cells through altered NK ligand expression, resulting in polyclonal metastases.

Controlling the selectivity of the chemical modification of a genetic-manipulation-free protein is currently problematic. Here the authors report a method using cysteine-based chemoselective Linchpin Directed site-selective Modification of the lysine residue in a protein.

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.

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.

Enteropathogenic bacteria use extracellular appendages, known as F-pili, to share plasmids carrying antibiotic resistance genes. Here, the authors show that F-pili are highly flexible but robust at the same time, and this is important for plasmid transfer and formation of biofilms that protect against the action of antibiotics.

Allosteric interactions are an important contributor to the catalytic properties of enzyme. Here the authors demonstrate—using the prototypical protein kinase PKA—that the allosteric cooperativity underscoring substrate recognition and product release are directly linked to changes in conformational entropy.

Studying the phase separation of small molecule systems provides a simplified framework for elucidating assembly pathways that may be obscured in macromolecular systems, but most studies focus on protein- or RNA-based condensates. Here, using nuclear magnetic resonance, the authors reveal that ATP, in the presence of Mg²⁺, undergoes phase separation coupled to percolation (PSCP), where the formation of 1:2 Mg²⁺–ATP nanoclusters precedes system-spanning networks and macroscopic condensation.

AcrB is a prototypical resistance–nodulation–division (RND) bacterial transporter, conferring resistance to a variety of antibiotics. HDX-MS and other, complementary approaches offer insight into AcrB structural dynamics and suggest the molecular mechanisms underlying drug export and inhibition of this multidrug-resistance conferring pump.

Lipid droplet (LD) function relies on protein partitioning between the endoplasmic reticulum (ER) and LD. The authors show that UBXD8 adopts distinct conformations in both membranes and undergoes structural rearrangements during ER-to-LD partitioning.

It remains challenging to gauge the gas-phase structure of biomolecular ions and assess to what extent native-like structures are maintained. Here, the authors utilize Förster resonance energy transfer and ion mobility spectrometry for more stringent structural characterization of biomolecular ions.

PCR is an essential method for the amplification and manipulation of nucleic acids, but the requirement for a thermocycler limits access. Here, authors engineer a helicase to replace the heating step of PCR with enzymatic unwinding, allowing the isothermal amplification of fragments up to 6 kb.

A cryo-EM structure of the active human melatonin receptor in complex with G_i reveals conformational changes upon activation and the molecular basis for G-protein selectivity.

Host proteins CPSF6, NUP153, and SEC24C are vital for HIV-1 infection. They bind to the viral capsid protein and contribute to shuttling of virions through the cytoplasm (SEC24C), import into the nucleus (NUP153 and CPSF6) and subsequent trafficking to preferred integration sites (CPSF6). Here, Wei et al. combine structural, biochemical and virological assays to emphasize the importance of prion-like low complexity domains surrounding short phenylalanine-glycine regions in binding and increasing the avidity when interacting with viral capsid.

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.

In layered transition metal oxides as cathode active materials for Na-ion batteries, Na⁺ diffusion kinetics are impacted by Na⁺/vacancy ordering. Here, the authors suggest that the P2-type Na_2/3Ni_1/3Mn_2/3O₂ with large zigzag ordering exhibits high Na⁺ mobility and thus superior rate capability.

Target membrane poration is a longstanding enigma in virology. Here, authors show that fusion peptides of the influenza virus’ spike protein aggregate, rotate, and tilt in membranes, facilitating peptide-induced poration during viral fusion.

Here, the authors present four high-resolution structures of SyHR protein from cyanobacterial anion pumps family: chloride and sulfate bound forms and two active state structures. These structures provide insights into the molecular mechanisms of SyHR and cyanobacterial anion pumps in general.

Energy coupling factor (ECF) transporters are responsible for the uptake of micronutrients and consist of an integral membrane unit, the S-component, which confers substrate specificity. Here, authors present multi-scale molecular dynamics simulations and in vitro experiments to study the molecular toppling mechanism of the S-component of a folate-specific ECF transporter.

Prew et al. uncovered a structural basis for human VLCAD deficiency that arises from point mutations within the enzyme’s membrane-binding region, which was shown to fold as a putative α-helical hairpin. Helix-breaking mutations selectively disrupt membrane interaction and thus homeostatic function.

We propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5, including a series of structures in lipid nanodiscs, from inactive to fully active, with agonist-bound intermediate states.

Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.

So far most of the de novo designed proteins are for single states only. Here, the authors present the de novo design and crystal structure determination of a coiled-coil peptide that assembles into multiple, distinct conformational states under the same conditions and further characterise its properties with biophysical experiments, NMR and MD simulations.

The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.

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.

The complete conformational cycle of RNA translocation by Prp43 is revealed in atomic detail from molecular dynamics simulations.

Epigallocatechin gallate (EGCG) is a catechin flavonoid which induces apoptosis in cancerous cells, but the underlying molecular mechanisms remain poorly understood. Here authors use an interdisciplinary approach to show a direct interaction between EGCG and the tumor suppressor p53 and demonstrate that EGCG inhibits ubiquitination of p53 by MDM2.

Chemigenetic combination of a synthetic ion-recognition motif and a protein-based fluorophore resulted in the development of calcium and sodium ion sensors.

Outer hair cell electromotility, driven by prestin, is essential for mammalian cochlear amplification. Here, the authors report the cryo-EM structures of thermostabilized prestin in the presence of various anions, providing insight into the mechanisms of mammalian cochlear amplification.

Peptide design remains a challenge owing to the large library of amino acids. Rational design approaches, although successful, result in a peptide design bias. Now it has been shown that AI techniques can be used to overcome such bias and discover unusual peptides as efficiently as humans.

The Legionella collagen-like protein (Lcl) is important for host adhesion in Legionella pneumophila. Here, the authors provide structural and biochemical data, which provides insights into a distinct “fuzzy” glycosaminoglycan binding mechanism.

The Eyes Absent proteins (EYA1-4) are a group of tyrosine phosphatases. Here, the authors report a signalling pathway in which EYA4 and EYA1 dephosphorylate Polo-like kinase 1 (PLK1) at pY445 to support PLK1 activation and mitosis.

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.

This paper reports on two mycobacterial glycerolipid acyltransferases capable of transferring acyl chains to position 1 or position 2 of both glycerol-3-phosphate and lysophosphatidic acid.

Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.

Cryo-electron microscopy structures of mouse trace amine-associated receptor 9 reveals structural motifs involved in odorant ligand recognition, including a unique disulfide bond linking the N terminus to extracellular loop 2.

Bacterial hairs called pili become highly-conductive electric wires upon addition of both natural and synthetic amino acids conjugated with gold nanoparticles. Here the authors use computationally-guided ordering further increasing their conductivity, thus yielding genetically-programmable materials.

Human disease mutations affect protein–protein interfaces in a three-dimensional structurally resolved interaction network. Predicted oncoPPIs in cancer correlate with survival and drug sensitivity, and affect growth in vitro, supporting their relevance to disease pathogenesis.

Models of the origin of life generally require a mechanism to structure emerging populations. Here, Krieger et al. develop spatial models showing that coherent structures arising in turbulent flows in aquatic environments could have provided compartments that facilitated the origin of life.

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.

Cryo-EM analysis with DEER spectroscopy and molecular dynamics simulations of the ABC exporter BmrCD reveal dual-mode substrate binding in an ATP- and substrate-bound state.

Identification of a small molecule (Ebio1) reveals a unique activation mechanism for the KCNQ2 potassium channel. Ebio1 induces a twist-to-open movement in the S6 helices, creating an extended channel gate with enhanced conductance.

The condensation of RNA polymerase II (Pol II) into transcriptionally active clusters is critical for eukaryotic gene regulation and pre-mRNA transcription. Here the authors show that a tight network of tyrosine-proline interactions imparts temperature and concentration-dependent self-coacervation of Pol II’s C-terminal domain (CTD).

Asc1/CD98hc is a key regulator of small neutral amino acid transport in the brain and adipose tissue. Here, authors report the structure of semi-occluded hAsc1/CD98hc and provide a model for Asc1 exchange and facilitated diffusion modes of transport.