MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition.
Rebecca C CollJames R HillChristopher J DayAlina ZamoshnikovaDave BoucherNicholas L MasseyJessica L ChittyJames A FraserMichael P JenningsAvril A B RobertsonKate SchroderPublished in: Nature chemical biology (2019)
Inhibition of the NLRP3 inflammasome is a promising strategy for the development of new treatments for inflammatory diseases. MCC950 is a potent and specific small-molecule inhibitor of the NLRP3 pathway, but its molecular target is not defined. Here, we show that MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation.