The Inflammasome Lab have defined the molecular target of MCC950, revealing the mechanism by which this potent and specific small-molecule inhibitor inhibits the NLRP3 inflammasome.
Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, Chitty JL, Fraser J, Jennings MP, Robertson AAB, Schroder K. (2019).
MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nature Chemical Biology 8(1):8618. Pubmed PDF
MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.
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.
Another article MCC950 closes the active conformation of NLRP3 to an inactive state was published back to back in the same edition of Nature Chemical Biology, alongside a Brief Communication on both articles.
This research was also featured in IMB News.
Image: Graphical abstract showing the MCC950 target region within the NLRP3 Walker B motif that mediates inflammasome inhibition.
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