XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity

The human MT1 and MT2 melatonin receptors1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns3. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer3, and MT2 has also been implicated in type 2 diabetes4,5. Here we report X-ray free electron laser (XFEL) structures of the human MT2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H2085.46A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature7) and N862.50D, obtained in complex with 2-PMT. Comparison of the structures of MT2 with a published structure8 of MT1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [3H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT1 and MT2, but in addition the MT2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT2. Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents. © 2019, The Author(s), under exclusive licence to Springer Nature Limited

Structural basis of ligand recognition at the human MT1 melatonin receptor

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms1 by synchronization to environmental cues and is involved in diverse physiological processes2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function3. Melatonin is formed in the pineal gland in a light-regulated manner4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT1) and type 1B (MT2)3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden7. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids8,9, and is one of the most popular supplements in the United States10. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT1 in complex with four agonists: the insomnia drug ramelteon11, two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine12,13. The structure of MT2 is described in an accompanying paper14. Although the MT1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT1, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors

Publisher Correction: Structural basis of ligand recognition at the human MT1 melatonin receptor (Nature, (2019), 569, 7755, (284-288), 10.1038/s41586-019-1141-3)

Change history: In this Letter, the rotation signs around 90°, 135° and 15° were missing and in the HTML, Extended Data Tables 2 and 3 were the wrong tables; these errors have been corrected online. © 2019, The Author(s), under exclusive licence to Springer Nature Limited

Sleep duration, physical activity, and caloric intake are related to weight status in Mexican American children: a longitudinal analysis

Background: Obesity is a serious issue, spanning all ages, and, in the U.S., disproportionately affects Latinos and African Americans. Understanding sleep, physical activity and dietary behaviors that may predict childhood obesity can help identify behavioral intervention targets. Methods: Data were drawn from a U.S. cohort study of 323 Mexican American 8–10-year-old children and their mothers, who participated in a longitudinal study over a 2-year period. Measures were collected at baseline (BL; child mean age = 8.87, SD = 0.83), year 1 (FU1) and year 2 (FU2). Mothers reported on household income and acculturation at BL. Child height and weight were collected and BMI z-scores (BMIz) were calculated for weight status at BL, FU1, and FU2. Accelerometer-estimated sleep duration (hours) and moderate-to-vigorous physical activity (MVPA; minutes) were collected across 3 days at BL, FU1, and FU2. Two 24-h dietary recalls were performed at each time point; from these, average energy intake (EI, kcals/day) was estimated. Cross-lagged panel analysis was used to examine behavioral predictors on BMIz at each time point and across time. Results: At BL and FU1, longer sleep duration (β = − 0.22, p < 0.001; β = − 0.17, p < 0.05, respectively) and greater MVPA (β = − 0.13, p < 0.05; β = − 0.20, p < 0.01, respectively) were concurrently related to lower BMIz. At FU2, longer sleep duration (β = − 0.18, p < 0.01) was concurrently related to lower BMIz, whereas greater EI (β = 0.16, p < 0.01) was related to higher BMIz. Longer sleep duration at BL predicted lower BMIz at FU1 (β = − 0.05, p < 0.01). Conclusions: Longer sleep duration was concurrently related to lower weight status at each time point from ages 8–10 to 10–12. Higher MVPA was concurrently related to lower weight status in earlier childhood (ages 8–10 and 9–11) and higher EI was concurrently related to higher weight status toward the end of childhood (ages 10–12 years). Furthermore, longer sleep in earlier childhood was protective of children’s lower weight status 1 year later. These findings suggest that sleep duration plays a consistent and protective role against childhood obesity; in addition, MVPA and healthy EI remain important independent factors for obtaining a healthy weight. © 2021, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Clinical risk factors of adverse outcomes among women with COVID-19 in the pregnancy and postpartum period: A sequential, prospective meta-analysis.

This sequential, prospective meta-analysis (sPMA) sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to: disease severity, maternal morbidities, neonatal mortality and morbidity, adverse birth outcomes. We prospectively invited study investigators to join the sPMA via professional research networks beginning in March 2020. Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area. We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a two-stage meta-analysis. We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities (pre-existing diabetes, hypertension, cardiovascular disease) versus those without were at higher risk for COVID-19 severity and pregnancy health outcomes (fetal death, preterm birth, low birthweight). Participants with COVID-19 and HIV were 1.74 times (95% CI: 1.12, 2.71) more likely to be admitted to the ICU. Pregnant women who were underweight before pregnancy were at higher risk of ICU admission (RR 5.53, 95% CI: 2.27, 13.44), ventilation (RR 9.36, 95% CI: 3.87, 22.63), and pregnancy-related death (RR 14.10, 95% CI: 2.83, 70.36). Pre-pregnancy obesity was also a risk factor for severe COVID-19 outcomes including ICU admission (RR 1.81, 95% CI: 1.26,2.60), ventilation (RR 2.05, 95% CI: 1.20,3.51), any critical care (RR 1.89, 95% CI: 1.28,2.77), and pneumonia (RR 1.66, 95% CI: 1.18,2.33). Anemic pregnant women with COVID-19 also had increased risk of ICU admission (RR 1.63, 95% CI: 1.25, 2.11) and death (RR 2.36, 95% CI: 1.15, 4.81). We found that pregnant women with comorbidities including diabetes, hypertension, and cardiovascular disease were at increased risk for severe COVID-19-related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly-known risk factors, including HIV infection, pre-pregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors