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

被引：914

作者：

Coll, Rebecca C. ^{[1
,2
]}

Hill, James R. ^{[1
,2
]}

Day, Christopher J. ^{[3
]}

Zamoshnikova, Alina ^{[1
,2
,9
]}

Boucher, Dave ^{[1
,2
,10
]}

Massey, Nicholas L. ^{[1
,2
]}

Chitty, Jessica L. ^{[4
,5
,6
,7
]}

Fraser, James A. ^{[4
]}

Jennings, Michael P. ^{[3
]}

Robertson, Avril A. B. ^{[1
,2
,8
]}

Schroder, Kate ^{[1
,2
,4
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, St Lucia, Qld, Australia

[2] Univ Queensland, IMB Ctr Inflammat & Dis Res, St Lucia, Qld, Australia

[3] Griffith Univ, Inst Glyc, Gold Coast, Qld, Australia

[4] Univ Queensland, Australian Infect Dis Res Ctr, Sch Chem & Mol Biosci, St Lucia, Qld, Australia

[5] Garvan Inst Med Res, Sydney, NSW, Australia

[6] Kinghorn Canc Ctr, Canc Div, Sydney, NSW, Australia

[7] UNSW Sydney, St Vincents Clin Sch, Fac Med, Sydney, NSW, Australia

[8] Univ Queensland, Sch Chem & Mol Biosci, St Lucia, Qld, Australia

[9] Univ Queensland, Translat Res Inst, Diamantina Inst, Brisbane, Qld, Australia

[10] Univ Lausanne, Dept Biochem, Epalinges, Switzerland

来源：

NATURE CHEMICAL BIOLOGY | 2019年 / 15卷 / 06期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

ACTIVATION; MECHANISM; CLEAVAGE; BINDING;

D O I：

10.1038/s41589-019-0277-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：556 / +

页数：8

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