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.
Coll, R. C., Hill, J. R., Day, C. J., Zamoshnikova, A., Boucher, D., Massey, N. L., Chitty, J. L., Fraser, J. A., Jennings, M. P., Robertson, A. A. B., & Schroder, K. (2019). MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nature Chemical Biology, 15, 556–559. https://doi.org/10.1038/s41589-019-0277-7