Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization, and affecting various downstream signalling pathways1,2. Although there is a wealth of structural information delineating the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-EM structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1ΔCT). We found that phosphorylation of NTSR1 was critical for obtaining a stable complex with βarr1ΔCT, and identified phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observed a phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared to a structure of rhodopsin-arrestin-1, our structure displays an approximately 85° rotation of arrestin relative to the receptor. These findings highlight both conserved aspects but also the plasticity of arrestin–receptor interactions.

Following agonist activation, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins2. Here we present a cryo-electron microscopy (cryo-EM) structure of β-arrestin 1 (βarr1) in complex with muscarinic acetylcholine-2-receptor (M2R) reconstituted in lipid nanodiscs. The M2R–βarr1 structure shows a multimodal network of flexible interactions, including binding of the βarr1 N domain to phosphorylated receptor residues and βarr1 finger loop insertion into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric Go protein structure3. Moreover, the cryoEM map reveals that the βarr1 C-domain edge engages the lipid bilayer. Through atomistic simulations, biophysical, biochemical, and cellular assays, we show that the C-edge is critical for stable complex formation, βarr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest the cooperative interactions of β-arrestin with both the receptor and phospholipid bilayer contribute to its functional versatility.

Glycans have diverse physiological functions, ranging from energy storage and structural integrity to cell signalling and the regulation of intracellular processes1. Although biomass-derived carbohydrates (such as (D)-glucose, (D)-xylose and (D)-galactose) are extracted on commercial scales, and serve as renewable chemical feedstocks and building blocks2,3, there are many hundreds of distinct monosaccharides that typically cannot be isolated from their natural sources and must instead be prepared through multistep chemical or enzymatic syntheses4,5. These ‘rare’ sugars feature prominently in bioactive natural products and pharmaceuticals, including many FDA-approved antiviral, antibacterial, anti-cancer and cardiac drugs6,7. Here we report the preparation of rare sugar isomers directly from biomass carbohydrates through site-selective epimerization reactions. Mechanistic studies establish that these reactions proceed under kinetic control, through sequential steps of hydrogen atom abstraction and hydrogen atom donation mediated by two distinct catalysts. This synthetic strategy provides concise and potentially extensive access to this valuable class of natural compounds.

For the past 150 years, the prevailing view of the local interstellar medium was based on a peculiarity known as Gould’s Belt1–4, an expanding ring of young stars, gas and dust, tilted about 20 degrees to the Galactic plane. Still, the physical relation between local gas clouds has remained practically unknown because the distance accuracy to clouds is of the same order as, or larger than, their sizes5–7. With the advent of large photometric surveys8 and astrometric survey9 this situation has changed10. Here we report the three-dimensional structure of all local cloud complexes. We find a narrow and coherent 2.7-kiloparsec arrangement of dense gas in the solar neighbourhood that contains many of the clouds thought to be associated with the Gould Belt. This finding is inconsistent with the notion that these clouds are part of a ring, disputing the Gould Belt model. The new structure comprises the majority of nearby star-forming regions, has an aspect ratio of about 1:20, and contains about three million solar masses of gas. Remarkably, the new structure appears to be undulating and its three-dimensional structure is well described by a damped sinusoidal wave on the plane of the Milky Way, with an average period of about 2 kiloparsecs and a maximum amplitude of about 160 parsecs.

Cohesin catalyses the folding of the genome into loops that are anchored by CTCF1. The molecular mechanism of how cohesin and CTCF structure the 3D genome has remained unclear. Here we show that a segment within the CTCF N terminus interacts with the SA2-SCC1 subunits of cohesin. A 2.6 Å crystal structure of SA2-SCC1 in complex with CTCF reveals the molecular basis of the interaction. We demonstrate that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF-binding sites. A similar motif is present in a number of established and novel cohesin ligands, including the cohesin release factor WAPL2,3. Our data suggest that CTCF enables chromatin loop formation by protecting cohesin against loop release. These results provide fundamental insights into the molecular mechanism that enables dynamic regulation of chromatin folding by cohesin and CTCF.

Metformin, the world’s most prescribed anti-diabetic drug, is also effective in preventing type 2 diabetes in people at high risk1,2. Over 60% of this effect is attributable to the ability of metformin to lower body weight in a sustained manner3. The molecular mechanisms by which metformin lowers body weight are unknown. In two, independent randomised controlled clinical trials, circulating levels of GDF15, recently described to reduce food intake and lower body weight through a brain stem-restricted receptor, were increased by metformin. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to a high-fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high-fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. Metformin retained its ability to lower circulating glucose levels in the absence of GDF15 action. In summary, metformin elevates circulating levels of GDF15, which are necessary for its beneficial effects on energy balance and body weight, major contributors to its action as a chemopreventive agent.

Microtubules (MTs) are dynamic polymers of αβ-tubulin and play critical roles in cell signaling, cell migration, intracellular transport processes and chromosome segregation1. They assemble de novo from α/β-tubulin dimers in an essential process termed MT nucleation. Complexes containing the protein γ-tubulin serve as structural templates for the MT nucleation reaction2. In vertebrates, MTs are nucleated by the 2.2 MDa γ-tubulin ring complex (γ-TuRC) composed of γ-tubulin, five related γ-tubulin complex proteins (GCP2-6) and additional factors3. GCP6 is unique among the GCP proteins, because it carries an extended insertion domain of unknown function. High-resolution structural information on the γ-TuRC is not available, strongly limiting our understanding of MT formation in cells and tissue2. Here, we present the cryo-EM structure of γ-TuRC from Xenopus laevis at 4.8 Å global resolution, revealing a 14-spoked arrangement of GCPs and γ-tubulins in a partially flexible open left-handed spiral with a uniform sequence of GCP variants (Fig. 1a). Via specific interactions with other GCP proteins, the GCP6-specific insertion domain scaffolds the assembly of the γ-TuRC. Unexpectedly, we identified Actin as a bona fide structural component of γ-TuRC with functional relevance in MT nucleation. The γ-TuRC spiral geometry is suboptimal for MT nucleation and a controlled conformational rearrangement of the γ-TuRC is required for its activation. Collectively, our cryo-EM reconstruction provides unprecedented insights into the molecular organization, the assembly and the activation mechanism of vertebrate γ-TuRC and will serve as an important framework for the mechanistic understanding of fundamental biological processes associated with MT nucleation, e.g. meiotic and mitotic spindle formation and centriole biogensis4.