Exploring inflammasome activation and targeted inhibition
Inflammasomes are cytosolic multi-protein complexes that form in response to a wide range of pathogens, tissue damage, and other harmful stimuli. Members of the family of NOD-like receptors (NLRs) sense these pathogen and danger a...
Inflammasomes are cytosolic multi-protein complexes that form in response to a wide range of pathogens, tissue damage, and other harmful stimuli. Members of the family of NOD-like receptors (NLRs) sense these pathogen and danger associated molecular patterns, triggering innate immune responses. NLRP3 is a well-studied NLR whose activation by a broad spectrum of stimuli leads to inflammasome formation and pyroptosis. Yet, the mechanisms inducing NLRP3 activation and the way how antagonistic small molecules counteract its function remain poorly understood. Just recently, we have determined the cryo-electron microscopy structures of full-length human NLRP3 in its inactive form and bound to the inhibitor CRID3. Native NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers. We made the surprising finding that the effector pyrin domain is shielded inside the decamer cage providing a safeguard mechanism against accidental activation. To obtain insights into the activation mechanism of NLRP3 and the molecular formation of the inflammasome, I here propose a challenging and pioneering endeavour: employing biochemical, biophysical and structural analyses, we will resolve the structure of activated NLRP3 associated to lipid membranes, unravel its regulation by post-translational modifications, design specific inhibitors for the targeted protein degradation, and explore filamentous seeds for the maturation of Caspase-1 and Alzheimer’s disease forming amyloid-beta fibrils. Further, transferring our knowledge of CRID3-mediated NLRP3 inhibition to other NLRs as NLRP12 and NLRP1 will shed light on their mechanism of action and open new avenues for directed targeting. Collectively, this work will uncover fundamental molecular principles of inflammasome activation and the mode of action of anti-inflammatory drugs. I foresee, that these insights will open a wide field for the development of NLR-specific inhibitors as new medicines.ver más
Seleccionando "Aceptar todas las cookies" acepta el uso de cookies para ayudarnos a brindarle una mejor experiencia de usuario y para analizar el uso del sitio web. Al hacer clic en "Ajustar tus preferencias" puede elegir qué cookies permitir. Solo las cookies esenciales son necesarias para el correcto funcionamiento de nuestro sitio web y no se pueden rechazar.
Cookie settings
Nuestro sitio web almacena cuatro tipos de cookies. En cualquier momento puede elegir qué cookies acepta y cuáles rechaza. Puede obtener más información sobre qué son las cookies y qué tipos de cookies almacenamos en nuestra Política de cookies.
Son necesarias por razones técnicas. Sin ellas, este sitio web podría no funcionar correctamente.
Son necesarias para una funcionalidad específica en el sitio web. Sin ellos, algunas características pueden estar deshabilitadas.
Nos permite analizar el uso del sitio web y mejorar la experiencia del visitante.
Nos permite personalizar su experiencia y enviarle contenido y ofertas relevantes, en este sitio web y en otros sitios web.