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NLRP3 monomer functional dynamics: From the effects of allosteric binding to implications for drug design

Articolo
Data di Pubblicazione:
2023
Abstract:
: The protein NLRP3 and its complexes are associated with an array of inflammatory pathologies, among which neurodegenerative, autoimmune, and metabolic diseases. Targeting the NLRP3 inflammasome represents a promising strategy for easing the symptoms of pathologic neuroinflammation. When the inflammasome is activated, NLRP3 undergoes a conformational change triggering the production of pro-inflammatory cytokines IL-1β and IL-18, as well as cell death by pyroptosis. NLRP3 nucleotide-binding and oligomerization (NACHT) domain plays a crucial role in this function by binding and hydrolysing ATP and is primarily responsible, together with conformational transitions involving the PYD domain, for the complex-assembly process. Allosteric ligands proved able to induce NLRP3 inhibition. Herein, we examine the origins of allosteric inhibition of NLRP3. Through the use of molecular dynamics (MD) simulations and advanced analysis methods, we provide molecular-level insights into how allosteric binding affects protein structure and dynamics, remodelling of the conformational ensembles populated by the protein, with key reverberations on how NLRP3 is preorganized for assembly and ultimately function. The data are used to develop a Machine Learning model to define the protein as Active or Inactive, only based on the analysis of its internal dynamics. We propose this model as a novel tool to select allosteric ligands.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Allostery; Molecular dynamics; Protein-protein interactions
Elenco autori:
Casali, Emanuele; Serapian, Stefano A; Gianquinto, Eleonora; Castelli, Matteo; Bertinaria, Massimo; Spyrakis, Francesca; Colombo, Giorgio
Autori di Ateneo:
BERTINARIA Massimo
GIANQUINTO Eleonora
SPYRAKIS Francesca
Link alla scheda completa:
https://iris.unito.it/handle/2318/1932330
Link al Full Text:
https://iris.unito.it/retrieve/handle/2318/1932330/1189288/2309.03589red.pdf
Pubblicato in:
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Journal
Progetto:
Protecting the brain from COVID-19-mediated neurodegeneration through inflammasome inhibition
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Settori (17)


LS2_11 - Bioinformatics and computational biology - (2022)

PE5_14 - Macromolecular chemistry - (2022)

CIBO, AGRICOLTURA e ALLEVAMENTI - Agricoltura e Produzioni Vegetali

CIBO, AGRICOLTURA e ALLEVAMENTI - Allevamento e Produzioni Animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Farmacologia Veterinaria

CIBO, AGRICOLTURA e ALLEVAMENTI - Miglioramento e difesa delle colture

CIBO, AGRICOLTURA e ALLEVAMENTI - Patologia e malattie degli animali

CIBO, AGRICOLTURA e ALLEVAMENTI - Scienze cliniche veterinarie

CIBO, AGRICOLTURA e ALLEVAMENTI - Tecnologie alimentari e microbiologia degli alimenti

INFORMATICA, AUTOMAZIONE e INTELLIGENZA ARTIFICIALE - Genetica, Omica e Bioinformatica

MEDICINA, SALUTE e BENESSERE - Epidemiologia

MEDICINA, SALUTE e BENESSERE - Malattie neurologiche e neurodegenerative

MEDICINA, SALUTE e BENESSERE - Oncologia e Tumori

MEDICINA, SALUTE e BENESSERE - Ricerca Traslazionale e Clinica

PIANETA TERRA, AMBIENTE, CLIMA, ENERGIA e SOSTENIBILITA' - Chimica e Ambiente

SCIENZE DELLA VITA e FARMACOLOGIA - Interazioni tra molecole, cellule, organismi e ambiente

SCIENZE MATEMATICHE, CHIMICHE, FISICHE - Materiali Avanzati
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