MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

TY - JOUR

T1 - MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition

AU - Coll, Rebecca C

AU - Hill, James R

AU - Day, Christopher J

AU - Zamoshnikova, Alina

AU - Boucher, Dave

AU - Massey, Nicholas L

AU - Chitty, Jessica L

AU - Fraser, James A

AU - Jennings, Michael P

AU - Robertson, Avril A B

AU - Schroder, Kate

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - Adenosine Triphosphate/antagonists & inhibitors

KW - Binding Sites/drug effects

KW - Heterocyclic Compounds, 4 or More Rings/chemistry

KW - Humans

KW - Hydrolysis/drug effects

KW - Inflammasomes/antagonists & inhibitors

KW - NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors

KW - Sulfones/chemistry

U2 - 10.1038/s41589-019-0277-7

DO - 10.1038/s41589-019-0277-7

M3 - Article

C2 - 31086327

SN - 1552-4450

VL - 15

SP - 556

EP - 559

JO - NATURE CHEMICAL BIOLOGY

JF - NATURE CHEMICAL BIOLOGY

IS - 6

ER -