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Nat Chem Biol. 2019 Jun;15(6):556-559. doi: 10.1038/s41589-019-0277-7. Epub 2019 May 13.

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

Author information

1
Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Queensland, Australia. r.coll@qub.ac.uk.
2
Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Queensland, Australia.
3
Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia.
4
Translational Research Institute, The University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.
5
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
6
Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
7
The Garvan Institute of Medical Research & the Kinghorn Cancer Centre, Cancer Division, Sydney, New South Wales, Australia.
8
St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.
9
Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Queensland, Australia. a.robertson3@uq.edu.au.
10
School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. a.robertson3@uq.edu.au.
11
Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Queensland, Australia. k.schroder@imb.uq.edu.au.
12
Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. k.schroder@imb.uq.edu.au.

Abstract

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.

Comment in

PMID:
31086327
DOI:
10.1038/s41589-019-0277-7
[Indexed for MEDLINE]

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