Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor

The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics. A crystal structure of the active κ-opioid receptor provides a guide for the development of safe and effective new analgesics. © 2017 Elsevier Inc

Structural determinants of 5-HT2B receptor activation and biased agonism

Serotonin (5-hydroxytryptamine; 5-HT) receptors modulate a variety of physiological processes ranging from perception, cognition and emotion to vascular and smooth muscle contraction, platelet aggregation, gastrointestinal function and reproduction. Drugs that interact with 5-HT receptors effectively treat diseases as diverse as migraine headaches, depression and obesity. Here we present four structures of a prototypical serotonin receptor—the human 5-HT2B receptor—in complex with chemically and pharmacologically diverse drugs, including methysergide, methylergonovine, lisuride and LY266097. A detailed analysis of these structures complemented by comprehensive interrogation of signaling illuminated key structural determinants essential for activation. Additional structure-guided mutagenesis experiments revealed binding pocket residues that were essential for agonist-mediated biased signaling and β-arrestin2 translocation. Given the importance of 5-HT receptors for a large number of therapeutic indications, insights derived from these studies should accelerate the design of safer and more effective medications. © 2018, The Author(s)

Adecuación entre Enseñanza Universitaria Técnica y sistema productivo

Desde una perspectiva doble (Sistema Productivo y Sistema Educativo) el trabajo analiza con detalle la adecuación entre ambos sistemas, intentando extraer datos que permitan mejorarla. Alumnos de último curso de Facultades, Escuelas Técnicas Superiores y de grado medio (n=337 sujetos. Error +/- 0'052) y empresas catalanas (n=180 empresas. Error 0'073. Nivel de confianza del 95 por ciento). Aplicación de encuestas de opinión a alumnos (entrevista directa) y a directivos y personal de empresas (encuestas por correo, tasa de devolución del 36 por ciento). Se evalúan las opiniones de ambos colectivos sobre los temas de adecuación entre Sistema Educativo y Productivo. Cuestionario ad hoc para alumnos con 19 ítems de respuesta cerrada. Cuestionario ad hoc para personal de empresas con 15 ítems de respuesta cerrada. Tablas de frecuencia. El alumno tipo es hombre, con edad entre 22 y 25 años y soltero. A veces compagina trabajo y estudios (éstos han sido elegidos por cuestiones vocacionales y de autorrealización). La mayoría considera que existe una gran inadecuación entre planes de estudio (demasiado teóricos) y exigencias de mercado y sugieren realzar los aspectos prácticos y concertar acuerdos de inserción con las empresas. Sus canales de búsqueda de empleo son la prensa y los contactos personales antes que los canales institucionales. Los puestos que más aprecian son los de investigación y de dirección. Por su parte, las empresas reclutan mayoritariamente a través de la prensa. Su perfil ideal no se decanta por la especialización o por la formación general. Se valoran mucho los aspectos psicológicos seguidos de la experiencia previa. Consideran necesario una colaboración entre la empresa y la Universidad y como vía de inserción laboral el contrato en prácticas. El trabajo recomienda desarrollar planes de estudio más prácticos, reformar los marcos legales para facilitar contratos en prácticas y potenciar los canales institucionales para obtener empleo. En estos puntos la opinión de empresarios y estudiantes coincide. El trabajo incluye amplios anexos legislativos y estadísticos.CataluñaBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; Fax +34917748026; [email protected]

Structural basis of ligand recognition at the human MT1 melatonin receptor

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms by synchronization to environmental cues and is involved in diverse physiological processes such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function. Melatonin is formed in the pineal gland in a light-regulated manner by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness by activating two high-affinity G-protein-coupled receptors, type 1A (MT$_1$) and type 1B (MT$_2$). 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 burden. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids, and is one of the most popular supplements in the United States. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT$_1$ in complex with four agonists: the insomnia drug ramelteon, two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine. The structure of MT$_2$ is described in an accompanying paper. Although the MT$_1$ 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 MT$_1$, 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 MT$_1$ 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