Explore the vast range of titles available.

Glutamate transporters couple the uptake of glutamate to the transport of cations. A new crystal structure of an archaeal trimeric glutamate transporter homolog, GltPh, captured in an intermediate conformation between the outward and inward facing states, provides insights into the transport mechanism. We report a structure of a trimeric glutamate transporter homolog from Pyrococcus horikoshii with two protomers in an inward facing state and the third in an intermediate conformation between the outward and inward facing states. The intermediate shows a cavity in the thinnest region of the transporter, which is potentially accessible to extracellular and cytoplasmic solutions. Our findings suggest a structural principle by which transport intermediates may mediate uncoupled permeation of polar solutes.

We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFold2 modelling, identifies T89 2.64 as important in the ELA binding site, and R168 4.64 as forming extensive interactions with the C-termini of both peptides. Base editing to introduce an R/H168 4.64 variant into human stem cell-derived cardiomyocytes demonstrates that this residue is critical for receptor binding and function. Additionally, we present an apelin receptor crystal structure bound to the G protein-biased, small molecule agonist, CMF-019, which reveals a deeper binding mode versus the endogenous peptides at lipophilic pockets between transmembrane helices associated with GPCR activation. Overall, the data provide proof-of-principle for using genetic variation to identify key sites regulating receptor-ligand engagement. This study explores apelin receptor’s role in cardiovascular function, identifying residues critical for binding through genetic variants, AlphaFold2 modelling and base editing in cardiomyocytes. Co-crystallization with biased agonist CMF-019 shows a unique binding mode versus endogenous peptides.

The altered activity of the fructose transporter GLUT5, an isoform of the facilitated-diffusion glucose transporter family, has been linked to disorders such as type 2 diabetes and obesity. GLUT5 is also overexpressed in certain tumour cells, and inhibitors are potential drugs for these conditions. Here we describe the crystal structures of GLUT5 from Rattus norvegicus and Bos taurus in open outward- and open inward-facing conformations, respectively. GLUT5 has a major facilitator superfamily fold like other homologous monosaccharide transporters. On the basis of a comparison of the inward-facing structures of GLUT5 and human GLUT1, a ubiquitous glucose transporter, we show that a single point mutation is enough to switch the substrate-binding preference of GLUT5 from fructose to glucose. A comparison of the substrate-free structures of GLUT5 with occluded substrate-bound structures of Escherichia coli XylE suggests that, in addition to global rocker-switch-like re-orientation of the bundles, local asymmetric rearrangements of carboxy-terminal transmembrane bundle helices TM7 and TM10 underlie a ‘gated-pore’ transport mechanism in such monosaccharide transporters. This study has determined the X-ray crystal structures of GLUT5 from Rattus norvegicus in an open, outward-facing conformation and GLUT5 from Bos taurus in an open, inward-facing conformation; comparison of these structures with previously published structures of the related Escherichia coli d -xylose:H + symporter XylE suggests that transport in GLUT5 is controlled by both a global ‘rocker-switch’-type motion and a local ‘gated-pore’-type transport mechanism. Structure of fructose transporter GLUT5 SLC2 family glucose transporters (GLUTs) facilitate the transport of glucose and other monosaccharides across biological membranes. GLUT5, which is fructose-specific, has been linked to disorders such as type 2 diabetes and obesity and is overexpressed in certain tumour cells. The authors solve X-ray crystal structures of GLUT5 from the brown rat in an open, outward-facing conformation and GLUT5 from cattle in an open, inward-facing conformation. Comparison of these structures with previously published structures of the related XylE, a proton-coupled sugar transporter from Escherichia coli , suggest that transport in GLUT5 is controlled by both 'rocker-switch' and 'gated-pore' type transport mechanisms. Also in this issue of Nature , Dong Deng et al . solve the X-ray crystal structures of human GLUT3 in outward-open and outward-occluded conformations.

Membrane transporters that clear the neurotransmitter glutamate from synapses are driven by symport of sodium ions and counter-transport of a potassium ion. Previous crystal structures of a homologous archaeal sodium and aspartate symporter showed that a dedicated transport domain carries the substrate and ions across the membrane. Here, we report new crystal structures of this homologue in ligand-free and ions-only bound outward- and inward-facing conformations. We show that after ligand release, the apo transport domain adopts a compact and occluded conformation that can traverse the membrane, completing the transport cycle. Sodium binding primes the transport domain to accept its substrate and triggers extracellular gate opening, which prevents inward domain translocation until substrate binding takes place. Furthermore, we describe a new cation-binding site ideally suited to bind a counter-transported ion. We suggest that potassium binding at this site stabilizes the translocation-competent conformation of the unloaded transport domain in mammalian homologues. Molecules of glutamate can carry messages between cells in the brain, and these signals are essential for thought and memory. Glutamate molecules can also act as signals to build new connections between brain cells and to prune away unnecessary ones. However, too much glutamate outside of the cells kills the brain tissue and can lead to devastating brain diseases. In a healthy brain, special pumps called glutamate transporters move these molecules back into the brain cells, where they can be stored safely. However, when brain cells are damaged—by, for example, a stroke or an injury,—the glutamate stored inside spills out, killing the surrounding cells. This leads to a cascade of dying cells and leaking glutamate, which causes even more damage and slows the recovery. Glutamate transporters ensure that there are more glutamate molecules inside cells than outside. However, it requires energy to maintain this gradient in the concentration of glutamate molecules. The transporters get this energy by moving three sodium ions into the cell with each glutamate molecule, and moving one potassium ion out of the cell. However, it is not clear how these transporters ensure that they move the glutamate molecules and the sodium ions at the same time. Now, Verdon, Oh et al. have uncovered the 3D structure of a glutamate transporter homologue at each step of the transport process. These structures reveal that, on the outside of the cell membrane, sodium ions attach to the so-called ‘transporter domain’ and make it better able to bind glutamate. The transporter domain then carries the sodium ions and glutamate through the cell membrane and releases them into the cell. Verdon, Oh et al. suggest that a potassium ion then binds to the empty transport domain, stabilizing it into a more compact shape that easily makes the return trip to the outside of the cell. Most experiments on glutamate transporters, including the work of Verdon, Oh et al., are carried out on model proteins taken from bacteria. An important challenge for the future will be to obtain structural information on human glutamate transporters, as these could be therapeutic targets for the treatment of various neurological conditions.

We report a structure of a trimeric glutamate transporter homologue from Pyrococcus horikoshii with two protomers in an inward facing state, and the third in an intermediate conformation between the outward and inward facing states. The intermediate shows a cavity in the thinnest region of the transporter, which is potentially accessible to the extracellular and cytoplasmic solutions. Our findings suggest a structural principle by which transport intermediates may mediate uncoupled permeation of polar solutes.

People living with sickle cell disease (SCD) face intermittent acute pain episodes due to vaso-occlusion primarily treated palliatively with opioids. Hemolysis of sickle erythrocytes promotes release of heme, which activates inflammatory cell adhesion proteins on endothelial cells and circulating cells, promoting vaso-occlusion. In this study, plasma-derived hemopexin inhibited heme-mediated cellular externalization of P-selectin and von Willebrand factor, and expression of IL-8, VCAM-1, and heme oxygenase-1 in cultured endothelial cells in a dose-responsive manner. In the Townes SCD mouse model, intravenous injection of free hemoglobin induced vascular stasis (vaso-occlusion) in nearly 40% of subcutaneous blood vessels visualized in a dorsal skin-fold chamber. Hemopexin administered intravenously prevented or relieved stasis in a dose-dependent manner. Hemopexin showed parallel activity in relieving vascular stasis induced by hypoxia-reoxygenation. Repeated IV administration of hemopexin was well tolerated in rats and non-human primates with no adverse findings that could be attributed to human hemopexin. Hemopexin had a half-life in wild-type mice, rats, and non-human primates of 80–102 h, whereas a reduced half-life of hemopexin in Townes SCD mice was observed due to ongoing hemolysis. These data have led to a Phase 1 clinical trial of hemopexin in adults with SCD, which is currently ongoing.

Background Patterns of steroid use in inflammatory bowel disease remain poorly characterized in real‐world settings. Steroid exposure is associated with adverse effects and often indicates suboptimally controlled disease. Therefore, patterns and predictors of steroid use in a large inflammatory bowel disease cohort were examined. Methods Steroid exposure over a 3‐year window was explored. Use was classified by duration—short (1–28 days), moderate (29–56 days), prolonged (> 56 days), and recency (within last year, prior years or no exposure). Associations with demographic and disease‐related factors were assessed using multivariable logistic regression. Results Among 5436 people (median age 42 years, IQR 32–56), 18.3% (n = 994) were steroid exposed. 57.6% had Crohn's disease and 50.2% were female. Crohn's disease was associated with lower odds of both prolonged and recent exposure compared to ulcerative colitis (AOR 0.72, p = 0.001 and AOR 0.78, p = 0.037, respectively). Females had a greater likelihood of both prolonged and recent exposure (AOR 1.22, p = 0.048 and AOR 1.23, p = 0.041, respectively). Young adults (20–29 years) had higher odds of prolonged and recent use than those > 70 years (AOR 6.59 and 9.12, respectively, p < 0.001). Combination immunomodulator and advanced therapy use was associated with a higher likelihood of both prolonged and recent use compared to 5‐aminosalicylic acid therapy alone (AOR 4.01, p = 0.002 and AOR 4.54, p < 0.001). Age at diagnosis had a modest effect size (AOR 1.03, p < 0.001). Conclusion Steroid use was modest, with over 80% unexposed over 3 years. Proactive optimization of therapy, particularly in younger individuals and those with ulcerative colitis, may further reduce steroid exposure.

Researchers at the University of Naples changed the diets of 23 patients for six months and measured the effect on their blood pressure. The patients, who were taking medication to control their hypertension (high blood pressure), were randomly divided into two groups. All were prescribed the same reduced-fat diet, except that one group used olive oil (high in mono-unsaturated fatty acids, or MUFA) and the other used sunflower oil (high in polyunsaturated fatty acids, or PUFA). Each patient followed one diet for six months and then switched to the other. Their blood pressure was periodically tested, and medication doses adjusted accordingly. After two months of the MUFA (olive oil) diet, patients needed less blood pressure medication, and there was a \"marked reduction\" in need after four months. \"The main result of our investigation was a straightforward reduction in antihypertensive tablet consumption when patients were given olive oil, whereas drug consumption was only mildly affected by sunflower oil,\" researchers said.

The Harvard University researchers froze blood samples from more than 28,000 healthy post-menopausal women and monitored the women for three years. They then analyzed the blood samples of 122 women in the group who subsequently suffered a heart attack or stroke, had undergone a heart bypass or angioplasty or died of cardiovascular disease. They also analyzed blood samples of 244 other women who did not suffer any cardiovascular problems. The researchers looked at 12 blood markers, including cholesterol and an indicator of inflammation called high sensitivity C-reactive protein. High levels of that protein turned out to be the best predictor of the risk of cardiovascular disease--even better than cholesterol screening. The study looked only at post-menopausal women and thus the results may not apply to younger women. Although the study does not specifically say the new findings would be relevant to men, the authors note that the earlier, smaller studies that also showed similar connections to arterial inflammation have largely focused on men. Also, since the blood samples were taken when the study began, it is not known how the women's blood markers might have changed over the course of the study. Nearly one in four Americans is infected with genital, or type 2, herpes simplex virus (HSV-2), but most don't know it. The virus, whose symptoms range from unrecognizably mild to painful, burning blisters in the genitals, is transmitted by sexual contact (or from mother to baby during childbirth). It had been assumed that people without symptoms were less likely to \"shed\" virus that could infect a sexual partner or a newborn. Researchers at the University of Washington found otherwise in a study of 53 people who tested positive for HSV-2 but had been unaware they had the infection. The 42 women and 11 men were tested daily for about three months to see if their genital secretions contained HSV-2 virus. Some 83 percent shed detectable virus, even though they had no history of symptoms.