H2020Индивидуална стипендия2018–2021

AlloGPCR · Allosteric modulation of G-protein Coupled Receptors conformational landscape

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2018-09-01 → 2021-08-31
Финансиране от ЕС: 246 668 €
Участници: 2
Схема: MSCA-IF-GF

Линиите свързват координатора с партньорите.

Накратко на български

Протеините-рецептори (GPCR), като тези за адреналина или грелина, се променят структурно, за да предадат сигнали в клетката. Разбирането на тези процеси помага за откриването на нови лекарства срещу затлъстяване, диабет и астма.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Allosteric modulation of G-protein Coupled Receptors conformational landscape

G protein–coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Ligand binding triggers a series of receptor conformational rearrangements, enabling the coupling to intracellular partners and the activation of signaling cascades. However, the molecular details of such mechanism remain elusive and additional data are required to shed light on the complex pharmacology of these receptors. The scope of the project is to address some fundamental open questions in the field: i) GPCR conformational dynamics and the impact of ligands, lipids and intracellular effectors ii) the role of the membrane environment on GPCR modulation. These aspects of GPCR signaling are still poorly understood but contribute to the complexity of the receptor signaling pathway, being crucial for the regulation of the spatial and temporal GPCR biological response in different tissues and cell types. Two receptor systems were used to address these questions: the beta2-adrenergic receptor (b2AR), a prototypical class A GPCR, and the ghrelin receptor or ghrelin hormone secretagogue receptor (GHSR). b2AR mediates its function in the heart and lungs and is the target of many drug compounds such as beta-blockers and anti-asthma medications. The ghrelin hormone secretagogue receptor (GHSR) is involved in important physiological processes and major diseases such as obesity and diabetes. No drugs are available at the moment to target the GHSR. Our efforts are directed to a better and more comprehensive understanding of the GPCR system. Our study contribute to the identification of drug candidates at the GHSR for the treatment of obesity and the development of the new generation drugs for the b2AR.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors in eukaryotes. They bind a wide range of ligands, such as neurotransmitters, hormones, lipids and many others. GPCRs are the target of more than 30% of the drugs currently on the market, addressing neuropsychiatric, cardiovascular, pulmonary and metabolic disorders, cancer, obesity and AIDS. The functional versatility of GPCRs cannot be explained by a simple two-state model of activation considering only an active and an inactive state, as these receptors are highly dynamic and can explore a wide range of conformations. Some receptors of the family can signal in the absence of ligand (basal activity), and despite GPCR have been largely studied in the past years, little is known about their signal transduction mechanism. Apart from ligands and signalling partners, the structure and function of GPCRs can be modulated by lipids. In this context, our research will be divided in two steps: delineating the role of lipids on GPCR conformational landscape at the molecular scale (Aim1) and exploring an additional allosteric factor in line with lipid composition, the homo- and hetero-receptor oligomerisation (Aim2). To that purpose, we will apply an integrated, multidisciplinary analysis, to characterize protein dynamics under physiological conditions, with the GPCR reconstituted in model lipid systems or living cells, and in the presence of ligands, signalling and regulatory partners. We will use conformational probes to investigate the effect of lipids and other GPCRs on receptor dynamics, and correlate these findings with functional properties such as agonist binding and G protein coupling.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITE DE MONTPELLIER · MontpellierКоординаторФранция
BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY · STANFORDСъединени щати