Open AccessStructural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation
Author(s) -
Umeharu Ohto,
Yukie Kamitsukasa,
Hanako Ishida,
Zhikuan Zhang,
Kazuyasu Murakami,
Chie Hirama,
Sakiko Maekawa,
Toshiyuki Shimizu
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2121353119
Subject(s) - inflammasome , pyrin domain , nod , chemistry , receptor , microbiology and biotechnology , biophysics , mode of action , cyclic nucleotide binding domain , biochemistry , nucleotide , biology , gene
Significance The 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.