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Cryo-electron microscopy snapshots of the E. coli flippase MsbA at discrete functional states reveal a ‘trap and flip’ mechanism for lipopolysaccharide flipping and the conformational transitions of MsbA during its substrate transport cycle.

Using a peptide toxin and small vanilloid agonists as pharmacological probes, high-resolution electron cryo-microscopy structures of rat TRPV1–ligand complexes are solved; these structures highlight conformational differences between TRP and voltage-gated ion channels in their active states, and suggest a dual gating mechanism that may account for the ability of members of the TRP channel superfamily to integrate diverse physiological signals.

A high-resolution electron cryo-microscopy structure of the rat transient receptor potential (TRP) channel TRPV1 in its ‘closed’ state is presented; the overall structure of this ion channel is found to share some common features with voltage-gated ion channels, although several unique, TRP-specific features are also characterized.

Cryo-electron microscopy structures and functional and mutagenesis studies provide insights into the catalysis of triacylglycerol synthesis by human acyl-CoA diacylglycerol acyltransferase at its intramembrane active site.

ROCK (RNA oligomerization-enabled cryo-EM via installing kissing loops) enables improved single-particle cryo-EM of RNAs. ROCK was used to generate high-quality structures of three diverse RNAs, including the Tetrahymena group I intron.

Sui et al. elucidate the mechanisms of action for small molecule inhibitors of human triacylglycerol synthesis enzyme DGAT1 and provide insights into how these inhibitors achieve selectivity for DGAT1 rather than other closely related MBOAT enzymes.

Wang et al. report a structure for human MBOAT7, the enzyme responsible for remodeling acyl chains of phosphatidylinositol. The structure enabled the identification of MBOAT7 inhibitors and provides insights into substrate specificity among MBOATs.

The cryo-electron microscopy structure of the gp120 component of the HIV-1 envelope glycoprotein, in complex with the primary receptor CD4 and coreceptor CCR5, provides insight into the cell-entry mechanism of HIV-1.

In Gram-negative bacteria, lipoproteins are transported from the inner membrane (IM) to the outer membrane (OM) by the ATP-binding cassette (ABC) transporter LolCDE. Here the authors present cryo-EM structures of nanodisc-embedded LolCDE in different states, providing mechanistic insight into the transport mechanism.

Cryo-electron microscopy structures of LptB₂FGC, in nucleotide-free and vanadate-trapped states, reveal the mechanism of lipopolysaccharide extraction from the inner membrane of Gram-negative bacteria and a role for LptC in efficient lipopolysaccharide transport.

ABCG2 is a human ABC transporter that actively extrudes a wide variety of compounds from cells but the mechanisms of multidrug transport remain obscure. Here authors present cryo-EM structures of ABCG2 in the apo state, and bound to the three structurally distinct chemotherapeutics and demonstrate how these molecules open the closed conformation of the transporter.

Here the authors determined structures of the mitochondrial ATP synthase at pH 6, in four distinct conformations. The structures represent intermediates in the reaction cycle of the enzyme and provide insights into its elastic coupling mechanism.

In this work, the authors determine the conformational ensemble of human P-glycoprotein during active drug transport using cryo-EM. This reveals key intermediate states and a peripheral substrate-binding site providing insights into P-glycoprotein’s transport mechanism.

X-ray and cryo-electron microscopy structures of fungal mitochondrial calcium uniporter proteins reveal a tetrameric architecture and shed light on the function of the channel.

Multidrug efflux pump EfpA is an essential protein for M. tuberculosis. The authors determine the structures of MtEfpA bound to lipids or the inhibitor BRD-8000.3, and propose it may function as a lipid flippase with a defined inhibition mechanism.

The retention of galactose-deficient IgA1 (Gd-IgA1) in the mesangium leads to pathogenesis in IgA nephropathy. Here the authors report that Gd-IgA1 is internalized by mesangial cells potentially via transferrin receptor 1, forming aggregates that disrupt lysosomal function and elicit inflammation.

Cryo-EM structures of the RAG endonuclease in complex with intact DNA substrates reveal that DNA melting is the first step in V(D)J recombination, a mechanism potentially conserved in retroviral integration and DNA transposition.

The cryo-EM structure of the zebrafish cation–chloride cotransporter NKCC1 reveals the domain organization, ion translocation pathway, ion-binding sites and key residues for binding activity, providing insights into the activity of this family of transporter proteins with key roles in physiology.

Cryo-electron microscopy reveals the structures of the mitochondrial calcium uniporter holocomplex in low- and high-calcium conditions, showing the gating mechanism that underlies uniporter activation in response to intracellular calcium signals.

Arlt et al. report a structure of yeast seipin, a lipid droplet formation protein, and suggest that it forms a flexible, oligomeric cage in the endoplasmic reticulum membrane, enabling triacylglycerol phase separation, lipid droplet growth and budding toward the cytoplasm.

The structure of yeast Hrd1 in complex with Hrd3 shows that Hrd1 forms an aqueous cavity with a lateral seal within the endoplasmic reticulum membrane, shedding light on how misfolded proteins are transported out of the endoplasmic reticulum.

Controlling the partial reduction of quinolines is challenging, given the competing overreduction to tetrahydroquinolines. Here, the authors report a cobalt-amido cooperative catalyst for the selective, partial transfer hydrogenation of quinolines to 1,2-dihydroquinolines with H₃N·BH₃ as reductant.

BAFF is an important cytokine for B cell survival, and is a therapeutic target for autoimmune disorders. Here the authors show that a 'flap' region of BAFF converts BAFFR binding events into survival signals and, with structural data, that this ‘flap’ differentially modulates binding of drugs such as belimumab or atacicept.

The Schizosaccharomyces pombe HP1 protein, Swi6, is shown to exist in an auto-inhibited state when unbound to chromatin, switching to a spreading-competent state upon binding to the HK9 methyl mark; disrupting this switch affects heterochromatin assembly and gene silencing.

Luo, Zhou et al. show that Bedaquiline (BDQ, Sirturo), approved to treat multi-drug-resistant tuberculosis, inhibits the yeast and human mitochondrial ATP synthases in addition to its intended target, the Mycobacterium tuberculosis ATP synthase. The structure of the mitochondrial ATP synthase bound to BDQ suggests a means to modify this inhibitor to increase its specificity for the M. tuberculosis  enzyme, thereby reducing its side effects for patients.