Cargando…

Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation

The NLRP3 inflammasome is a cytoplasmic complex that regulates the activation of inflammatory cytokines and, given its implication in a range of diseases, is an important therapeutic target. The cofactor ATP and the centrosomal kinase NEK7 are important for NLRP3 activation. Here we have constructed...

Descripción completa

Detalles Bibliográficos
Autores principales: El‐Sayed, Sherihan, Freeman, Sally, Bryce, Richard A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9601872/
https://www.ncbi.nlm.nih.gov/pubmed/36173167
http://dx.doi.org/10.1002/pro.4420
_version_ 1784817172087832576
author El‐Sayed, Sherihan
Freeman, Sally
Bryce, Richard A.
author_facet El‐Sayed, Sherihan
Freeman, Sally
Bryce, Richard A.
author_sort El‐Sayed, Sherihan
collection PubMed
description The NLRP3 inflammasome is a cytoplasmic complex that regulates the activation of inflammatory cytokines and, given its implication in a range of diseases, is an important therapeutic target. The cofactor ATP and the centrosomal kinase NEK7 are important for NLRP3 activation. Here we have constructed and simulated computational models of full‐length monomeric NLRP3 to shed light on the importance of NEK7 and cofactor interactions for its conformation and dynamics in aqueous solution. We find that molecular dynamics simulation reproduces well the features of the recently published cryo‐EM structure of the ADP‐bound NLRP3–NEK7 complex; on the removal of NEK7, the NLRP3 molecule adopts a more compact closed form during simulations. Replacement of ADP by ATP promotes a rearrangement of hydrogen‐bonding interactions, domain interfaces, and a degree of opening of the NLRP3 conformation. We also examine the dynamics of an acidic loop of the LRR domain of NLRP3, which samples in a region observed in the NEK7‐bound cryo‐EM structure but not in an oligomeric form of inactive NLRP3. During the molecular dynamics simulations of NLRP3, we find some plasticity in its topology that suggests access routes for ATP to the cofactor pocket not immediately evident from the existing NEK7‐bound cryo‐EM structure. These computed dynamical trajectories of NLRP3 provide insight into coordinates of deformation that may be key for cofactor binding and inflammasome activation.
format Online
Article
Text
id pubmed-9601872
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher John Wiley & Sons, Inc.
record_format MEDLINE/PubMed
spelling pubmed-96018722022-10-27 Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation El‐Sayed, Sherihan Freeman, Sally Bryce, Richard A. Protein Sci Full‐length Papers The NLRP3 inflammasome is a cytoplasmic complex that regulates the activation of inflammatory cytokines and, given its implication in a range of diseases, is an important therapeutic target. The cofactor ATP and the centrosomal kinase NEK7 are important for NLRP3 activation. Here we have constructed and simulated computational models of full‐length monomeric NLRP3 to shed light on the importance of NEK7 and cofactor interactions for its conformation and dynamics in aqueous solution. We find that molecular dynamics simulation reproduces well the features of the recently published cryo‐EM structure of the ADP‐bound NLRP3–NEK7 complex; on the removal of NEK7, the NLRP3 molecule adopts a more compact closed form during simulations. Replacement of ADP by ATP promotes a rearrangement of hydrogen‐bonding interactions, domain interfaces, and a degree of opening of the NLRP3 conformation. We also examine the dynamics of an acidic loop of the LRR domain of NLRP3, which samples in a region observed in the NEK7‐bound cryo‐EM structure but not in an oligomeric form of inactive NLRP3. During the molecular dynamics simulations of NLRP3, we find some plasticity in its topology that suggests access routes for ATP to the cofactor pocket not immediately evident from the existing NEK7‐bound cryo‐EM structure. These computed dynamical trajectories of NLRP3 provide insight into coordinates of deformation that may be key for cofactor binding and inflammasome activation. John Wiley & Sons, Inc. 2022-09-21 2022-10 /pmc/articles/PMC9601872/ /pubmed/36173167 http://dx.doi.org/10.1002/pro.4420 Text en © 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full‐length Papers
El‐Sayed, Sherihan
Freeman, Sally
Bryce, Richard A.
Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title_full Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title_fullStr Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title_full_unstemmed Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title_short Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation
title_sort probing the effect of nek7 and cofactor interactions on dynamics of nlrp3 monomer using molecular simulation
topic Full‐length Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9601872/
https://www.ncbi.nlm.nih.gov/pubmed/36173167
http://dx.doi.org/10.1002/pro.4420
work_keys_str_mv AT elsayedsherihan probingtheeffectofnek7andcofactorinteractionsondynamicsofnlrp3monomerusingmolecularsimulation
AT freemansally probingtheeffectofnek7andcofactorinteractionsondynamicsofnlrp3monomerusingmolecularsimulation
AT brycericharda probingtheeffectofnek7andcofactorinteractionsondynamicsofnlrp3monomerusingmolecularsimulation