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Conformational studies of highly dynamic viral replication complexes

Description du projet

Découvrir l’ordre caché dans le désordre apparent peut favoriser le développement de médicaments ciblés

Les paramyxovirus sont responsables de nombreuses affections respiratoires et de nombreuses maladies infantiles courantes, comme la rougeole et les oreillons. Aux États-Unis, le virus respiratoire syncytial (VRS) humain est la principale cause d’hospitalisation des nourrissons. L’élaboration de vaccins constitue une priorité pour l’Organisation mondiale de la santé, car il n’existe pas de médicaments efficaces pour traiter les maladies à paramyxovirus. Un trouble inhabituel du complexe réplicatif des paramyxovirus pourrait constituer une cible potentielle pour de nouvelles thérapies, mais la caractérisation préalable des changements conformationnels dynamiques dans le principe de réplication s’est révélée difficile. Le projet DynamicAssemblies, financé par l’UE, prévoit d’élucider ce principe avec une résolution atomique sans précédent qui constitue la première étape décisive pour le développement ciblé de médicaments.

Objectif

Paramyxoviruses, including, measles and a number of dangerous human pathogens, are negative strand RNA viruses that express their own machinery for transcription and replication. Different interactions between the nucleoprotein (N) and the phosphoprotein (P) are essential for chaperoning and assembly of N on newly synthesized RNA genomes to form nucleocapsids (NCs), as well as for initiating replication and transcription. Both N and tetrameric P exhibit extensive conformational disorder, with very long, unfolded regions that host important post-translational modification sites as well as regulatory interactions with host and viral partners. The presence of this level of disorder, in viruses whose genetic information is normally so parsimoniously exploited, remains unexplained. The elaboration of time-resolved, atomic resolution descriptions of the interaction trajectories of these highly disordered N:P complexes is extremely challenging, requiring the development of adapted methodologies that can account for their intrinsic flexibility. The role of N and P has been rendered yet more enigmatic following our recent observation that when mixed in solution they form liquid-like droplets. Such membraneless organelles are revolutionizing our understanding of cellular chemical biology, although their physical basis is poorly understood. Our aim is to describe these important complexes at atomic resolution, in particular to understand the role of the extensive conformational dynamics of N and P in the replication cycle. Our recent success in engineering soluble N:P complexes from measles that assemble into NCs, combined with ongoing development of NMR-based methods to investigate the structure, dynamics and interaction kinetics of large, intrinsically disordered proteins, fluorescence spectroscopy, cryoEM, SAXS, crystallography and molecular simulation, will provide the essential tools to investigate the functional mechanisms of these previously inaccessible complexes.

Régime de financement

ERC-ADG - Advanced Grant

Institution d’accueil

COMMISSARIAT A L ENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES
Contribution nette de l'UE
€ 2 499 150,00
Adresse
RUE LEBLANC 25
75015 PARIS 15
France

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Région
Ile-de-France Ile-de-France Paris
Type d’activité
Research Organisations
Liens
Coût total
€ 2 499 150,00

Bénéficiaires (1)