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AK-42 was reported as a specific inhibitor of ClC-2 but its working mechanism is not clear. Here authors report cryo-EM structures of apo ClC-2 and in complex with AK-42, revealing how it inhibits ClC-2 specifically.

Combining expansion microscopy with super-resolution radial fluctuations captures the morphology of single proteins.

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.

Structural and biochemical studies of the Mycobacterium smegmatis hydrogenase Huc provides insights into how [NiFe] hydrogenases oxidize trace amounts of atmospheric hydrogen and transfer the electrons liberated via quinone transport.

SARS-CoV-2 main protease adapts a disulfide bonded inactive state to escape oxidative stress. Here, the authors report a crystal structure of an inactive conformation of the enzyme achieved through a H163A mutation, and the mechanistic details of conformational changes using atomistic simulations.

Temperature-induced insulator-to-metal transitions are usually accompanied by structural phase transitions. Here the authors demonstrate an enhancement of the electrical conductance in a thin film of a biologically relevant metal-organic framework, without noticeable change in the structure, assigned to be of mainly electronic origin.

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.

Toll-like receptors (TLRs) play a key role in the innate immune system. Here, Kornilov et al. resolve the 3D structures of the membrane-associated parts of four TLRs to reveal properties of the juxta-membrane domain.

A difference in the survival of respiratory chain complex III deficient Bcs1l^p.S78G mice was observed between two congenic mouse strains. Here the authors show how in one of the strains the combined effects of a spontaneously arising non-pathogenic variant and the disease-causing Bcs1l^p.S78G mutation exacerbate CIII deficiency and disease progression.

Second messengers regulate a broad spectrum of processes in bacteria. Here, authors characterize how the second messenger cyclic di-AMP inhibits the potassium transporter KimA using cryo-EM, molecular dynamics simulations and functional assays.

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.

A newly developed maternally selective nanobody antagonist against the angiotensin II type I receptor stabilizes the receptor in a hybrid conformation and simultaneously binds with specific small-molecule antagonists.

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.

Family 43 glycoside hydrolases (GH43) are involved in the breakdown of hemicellulose. Functional, structural and computational characterization of a GH43 enzyme, including a snapshot of an active Michaelis complex, reveal the hydrolysis mechanism and suggest two possible reaction pathways.

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.

P_1B-type ATPases export excess transition metals from cells. Here, the authors report a molecular structure of CopA, a coppertransporting P_1B-ATPase from A. fulgidus, in an inward-facing E1 conformation.

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.

Martini 3.0 is an updated and reparametrized force field for coarse-grained molecular dynamics simulations with new bead types and an expanded ability to model molecular packing and interactions.

Claudin family proteins are important for regulating epithelial barrier function. Here the authors show that claudin-23 controls paracellular flux by combining with other claudins to alter tight junction architecture and permeability.

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.

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.

Bacterial O antigen polysaccharides play a role in innate immune response evasion. Here, the authors uncover the ATP-bound structure of the Aquifex aeolicus WzmWzt O antigen ABC transporter, shedding light onto the mechanism of lipid-linked polysaccharide translocation.

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).

Disease-causing variants define a conserved and unique NR5A1 responsive enhancer for SRY expression to initiate testis-determination in humans. Modelling regulatory variants causing sex-reversal provides a tool to understand global enhancer activity.

Here the authors show that H2A.Z histone variant incorporation reduces the nucleosomal barrier for transcription. Furthermore their simulations reveal that H2A.Z facilitates spontaneous DNA unwrapping from the histone octamer and enhances nucleosome gaping.

Structures of human cholecystokinin receptors in complex with various ligands or G-proteins reveal how different ligand types are recognized and the basis of peptide selectivity in this receptor family, and suggest a stepwise activation mechanism.

The chaperone SurA is involved in outer membrane protein (OMP) biogenesis in Gram-negative bacteria, but its mechanism of action is not fully understood. Combining mass spectrometric, biophysical and computational approaches, the authors here show how the conformational dynamics of SurA facilitate OMP binding.

Vinculin binding to talin is a key event in focal adhesion dynamics; yet, how vinculin is activated to recruit actin remains unknown. Here, the authors use a multiscale approach to reveal that talin activates vinculin through an intricate allosteric mechanism tightly regulated by force.

Gangliosides such as GM1 present in the outer leaflet of the plasma membrane of eukaryotic cells are essential for many cellular functions and pathogenic interactions. Here the authors show that the acyl chain structure of GM1 determines the establishment of nanodomains when actively clustered by actin, which depended on membrane cholesterol and phosphatidylserine or superimposed by the GM1-binding bacterial cholera toxin.

How different oncogenic Akt mutants can affect the response to Akt inhibitors is currently unclear. Here, the authors analyse somatic mutations of Akt1-3 isoforms in several human cancers, investigate their oncogenic effects and therapeutic relevance in vitro and confirm some of their data in a clinical trial testing the AKT inhibitor capivasertib in patients with solid tumors harboring AKT alterations.

The membrane-shaping protein ARL6IP1 is involved in the selective degradation of the endoplasmic reticulum, and this process depends on its ubiquitination and interaction with other membrane-shaping proteins such as FAM134B.

Kemp eliminases are artificial enzymes that catalyze the concerted deprotonation and ring-opening of benzisoxazoles. Here, the authors use room-temperature X-ray crystallography to investigate changes to the conformational ensemble of the Kemp eliminase HG3 along a directed evolutionary trajectory, and develop an experimentally guided, ensemble-based computational enzyme design procedure.

Transmembrane proteins are important for cellular functions and synthetic analogues are of interest. Here the authors report on the design and testing of a synthetic multipass transmembrane channel which shows anisotropic responses to agonistic and antagonistic ligands.

The intrinsic disorder of histone tails poses challenges in their characterization. Here the authors apply extensive molecular dynamics simulations of the full nucleosome to show reversible binding to DNA with specific binding modes of different types of histone tails, where charge-altering modifications suppress tail-DNA interactions and may boost interactions between nucleosomes and nucleosome-binding proteins.

Glucagon-like peptide-1 receptor (GLP-1R) plays an important role in glucose homeostasis and treatment of type 2 diabetes. Here authors report the peptide-free crystal structure of human GLP-1R in an inactive state which reveals a unique closed conformation of the extracellular domain.

Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the γ-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function.

Mutation associated neoantigens are a family of highly specific therapeutic targets for the treatment of cancer. Here, the authors describe the cryo-EM structure of an antibody bound to a neoantigen complex providing insights into the specificity of the antibody.

Areas of HIV envelope (Env) that aren’t covered by glycans are potential targets for antibodies. Here, the authors computationally design small protein mimics of four such epitopes and show that they can induce Env binding antibodies in rabbits.

ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.

Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Here, authors present cryo-EM structures of the full-length glycine receptors (GlyRs) reconstituted into lipid nanodiscs in the unliganded, glycine-bound and allosteric modulator-bound conformations and reveal global conformational changes underlying GlyR channel gating and modulation.

Cryo-EM structures of human SERINC5 and its fly orthologue, along with extensive functional analyses, reveal the protein architecture and identify regions important for HIV-1 restriction.

Structural phase transitions are known to accommodate plastic deformation in some metals and ceramics. Here, the authors observe the in situtransformation of body-centred cubic molybdenum to face-centred cubic, and finally to body-centred cubic, allowing for 15.4% tensile strain accommodation.

The uptake of hydrophobic molecules by bacterial FadL channels is implicated in quorum sensing, interactions with eukaryotic hosts and biodegradation of many pollutants. Insights into monoaromatic hydrocarbon uptake by TodX and CymD channels suggest that all FadL channels mediate substrate uptake via lateral diffusion.

Tetraspanins play critical roles in various physiological processes, ranging from cell adhesion to virus infection. Here authors report the crystal structure of CD9 and the cryo-electron microscopic structure of CD9 in complex with its single membrane-spanning partner protein, EWI-2.

A hybrid machine learning–physics model is developed that reduces simulation cost by two orders of magnitude while retaining high ab initio accuracy, to predict free-energy transition states for hydrogen combustion reactions.

Superlubricity is important for energy and biomedical applications but typical building blocks are limited to synthetically-sourced polymeric materials. Here, self-assembly of plant-based protofilaments in biopolymeric hydrogels were engineered offering superlubricity performance.

In situ liquid-cell electrochemical transmission electron microscopy allows the direct visualization of the transformation of lithium polysulfides over electrode surfaces at the atomic scale, leading to a new energy-storage mechanism in lithium–sulfur batteries.