Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation

SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-spe...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 11; p. e2121353119
Main Authors Ohto, Umeharu, Kamitsukasa, Yukie, Ishida, Hanako, Zhang, Zhikuan, Murakami, Karin, Hirama, Chie, Maekawa, Sakiko, Shimizu, Toshiyuki
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 15.03.2022
Subjects
Alzheimer's disease
Animals
Arteriosclerosis
Atherosclerosis
Binding Sites
Biological Sciences
Conformation
Cryoelectron Microscopy
Diabetes mellitus
Domains
Drug delivery
Drug development
Electron microscopy
Inflammasomes
Inflammasomes - metabolism
Inhibitors
Membranes
Mice
Microscopy
Models, Molecular
Mutation
Neurodegenerative diseases
NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors
NLR Family, Pyrin Domain-Containing 3 Protein - chemistry
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Nucleotides
Oligomerization
Protein Binding
Protein Conformation
Protein Multimerization
Pyrin protein
Regulatory mechanisms (biology)
Structure-Activity Relationship
Transmission electron microscopy
NOD-like receptor
NLRP3
inflammasome
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Summary:SignificanceThe nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) is a pattern recognition receptor that forms an inflammasome. The cryo-electron microscopy structure of the dodecameric form of full-length NLRP3 bound to the clinically relevant NLRP3-specific inhibitor MCC950 has established the structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation and the mechanism of action of the NLRP3 specific inhibitor. The inactive NLRP3 oligomer represents the NLRP3 resting state, capable of binding to membranes and is likely disrupted for its activation. Visualization of the inhibitor binding mode will enable optimization of the activity of NLRP3 inflammasome inhibitor drugs.
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Edited by Hao Wu, Harvard Medical School, Boston, MA; received November 23, 2021; accepted January 19, 2022
Author contributions: U.O. designed research; U.O., Y.K., H.I., Z.Z., K.M., C.H., and S.M. performed research; U.O. analyzed data; and U.O., Y.K., and T.S. wrote the paper.
1U.O., Y.K., H.I. and Z.Z. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2121353119