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Biological membranes are tightly sealed. Here, Post and Hummer capture rare lipid flip-flop events and the formation of water nanopores across lipid bilayers with AI-guided simulations. The mechanism is encoded in close-to-linear neural networks.

As the recipients of the 2013 science Nobel prizes gather in Stockholm to celebrate and be celebrated, News & Views shares some expert opinions on the achievements honoured.

The fungal SND pathway inserts a wide range of proteins into the ER membrane. Here, SND3 is identified as a membrane insertase within a distinct SEC61 translocon complex, implying a role in co-translational insertion of multipass membrane proteins.

Structural analysis of the human choline and ethanolamine transporters FLVCR1 and FLVCR2 clarifies the mechanisms of transport, the conformational dynamics of these proteins and the disease-associated mutations that interfere with these processes.

Enabling visual proteomics with high-confidence 3D template matching (TM) in CryoET. 3D TM precisely localizes macromolecular complexes, individual subunits, and different functional states in situ, revealing molecular interactions within cells.

Adriaenssens et al. show that unlike soluble cargo receptors, transmembrane cargo receptors initiate autophagosome biogenesis by recruiting the FIP200/ULK1 or WIPI–ATG13 complex, revealing unexpected flexibility in the selective autophagy machinery.

Release of inorganic phosphate (P_i) from actin marks older actin filaments for disassembly. Here, the authors show how P_i exits the F-actin interior through a ‘molecular backdoor’. The backdoor arrangement is distorted in a disease-linked actin variant.

By combining single-molecule spectroscopy, nanophotonic enhancement, and molecular simulations, the authors reveal the extremely rapid chain dynamics of single-stranded nucleic acids.

KtrAB is a major potassium uptake system that has been linked to the pathogenesis of many infectious bacteria. Here the authors show that KtrB from Vibrio alginolyticus contains an intrinsically disordered N-terminus that is key to its regulation.

Combining high-speed AFM, single molecule recognition force spectroscopy, and molecular dynamics simulations Zhu, Canena, Sikora et al. characterize the interaction dynamics of the trimeric spike protein of SARS-CoV-2 wt, and delta and omicron variants with its entry receptor ACE2. While delta variant increases avidity by multivalent binding to ACE2, omicron variant shows an extended binding lifetime.

Cation-proton antiporters mediate selective ion exchange across cellular membranes to control pH, salt concentration and cell volume. Here the authors present a transition-path sampling method that overcomes the timescale gap between simulations (µs) and transport processes (s), which allows them to resolve the Na⁺ and H⁺ transport cycle of the Na⁺/H⁺ antiporter NhaP from Pyrococcus abyssi.

The SLC26 family of transporters maintains anion equilibria in all kingdoms of life. Here, the authors resolve the structure of an SLC26 dimer embedded in a lipid membrane and characterize it by PELDOR/DEER distance measurements, biochemical studies with MD simulations and spin-label ensemble refinement.

Previously shown as a 60-nm hole in the nuclear pore complex, the transport machinery by FG-nucleoporins is mapped.

FAM134B/RETREG1 is a selective ER-phagy receptor that regulates the size and shape of the endoplasmic reticulum. Here authors use molecular modeling and molecular dynamics simulations to assemble a structural model for the reticulon-homology domain of FAM134B.

Hydration is known to affect molecular-recognition processes, such as those between proteins and ligands. Now, theoretical simulations provide thermodynamic insight into cavity–ligand binding, revealing how it is predominantly driven by the behaviour of the few surrounding water molecules.

A machine learning algorithm speeds up the sampling of rare assembly events, discovers their mechanisms, extrapolates them across chemical and thermodynamic space, and condenses the learned assembly mechanisms into a human-interpretable form.

How can structural biology help us understand and combat SARS-CoV-2? Researchers in the field share their experiences and opinions and point to the challenges that lie ahead.

Cryo-electron microscopy and molecular dynamics studies of a Vitiosangium gasdermin pore reveal insights into the assembly of this large and diverse family of membrane pore-forming proteins.

LtaA catalyzes glycolipid translocation by a ‘trap-and-flip’ mechanism, pointing to a shared mechanistic model among MFS lipid transporters. Asymmetric lateral openings allow access of the entire lipid substrate to the amphipathic central cavity.

The biogenesis of nuclear pores imposes a logistic challenge for cells. Here, the authors investigate structural motifs for co-translational interactions in nucleoporins and find that co-translational assembly events differ between paralogous assembly pathways thus contributing to faithful assembly.

M. tuberculosis cytochrome bd oxidase is of interest as a TB drug target. Here, the authors present the 2.5 Å cryo-EM structure of M. tuberculosis cytochrome bd oxidase and identify a disulfide bond within the canonical quinol binding and oxidation domain (Q-loop) and a menaquinone-9 binding site at heme b₅₉₅.

Deep learning holds a great promise for the discovery and design of bioactive peptides, but experimental approaches to validate candidates in high throughput and at low cost are needed. Here, the authors combine deep learning and cell free biosynthesis for antimicrobial peptide (AMP) development and identify 30 functional AMPs, of which six with broad-spectrum activity against drug-resistant pathogens.

Ubiquitination of the receptor FAM134B regulates ER-phagy and remodelling of the endoplasmic reticulum in response to cellular demands.

Characterization of the conformation landscape of the bacterial ABC transporter CydDC reveals that this heterodimeric protein complex is a long-sought heme transporter essential for the functional maturation of bd-type cytochromes.

An integrated structural biology approach uncovers the structural complexity of the intrinsically disordered region (IDR) within the TRPV4 ion channel. Multiple stimulatory and inhibitory elements were identified within the IDR that modulate channel activity in a lipid-dependent manner.

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.

Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. Here authors reconstituted the core machinery for regulating lipid saturation in baker’s yeast to directly characterize its response to defined membrane environments and uncover its mode-of-action.

Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronavirus disease 2019 (COVID-19).

TAp63α monitors the genome integrity in oocytes. After DNA damage, TAp63α is activated, involving multiple phosphorylation steps by CK1 with different kinetics due to an unusual CK1/TAp63α interaction in which the product of one step inhibits the next.

Deep learning-based interpolation using cryoTIGER enhances angular sampling in cryoET, improving 3D reconstructions, particle localization, and structural recovery without increasing electron dose.

NMR and ITC are used to define essential features of a p38α phosphatase interface that extend beyond the classic KIM binding site, and SAXS analysis software, incorporating NMR chemical shift data, are developed and applied to build a model of the p38α-HePTP complex.

The glycosyltransferase PglH transfers three terminal N-acetylgalactosamine (GalNAc) residues to a carrier, which is a prerequisite for bacterial protein N-glycosylation. Here authors present the crystal structures of PglH in three distinct states and show that a ‘ruler helix’ facilitates membrane attachment and glycan counting.

In the Big Data era, a change of paradigm in the use of molecular dynamics is required. Trajectories should be stored under FAIR (findable, accessible, interoperable and reusable) requirements to favor its reuse by the community under an open science paradigm.

Eight cryo-electron microscopy structures of the ATP-binding cassette exporter TmrAB under turnover conditions characterize the entire transport cycle in a lipid environment.

New observations of ESCRT-mediated reverse-topology membrane scission are building towards a structural and biophysical explanation of the mechanism involved.