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

Rebecca C Coll¹, James R Hill², Christopher J Day³, Alina Zamoshnikova^{2

4}, Dave Boucher^{2

5}, Nicholas L Massey², Jessica L Chitty^{6

7

8}, James A Fraser⁶, Michael P Jennings³, Avril A B Robertson^{9

10}, Kate Schroder^{11

12}

Affiliations

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.

PMID: 31086327
DOI: 10.1038/s41589-019-0277-7

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

Rebecca C Coll et al. Nat Chem Biol. 2019 Jun.

. 2019 Jun;15(6):556-559.

doi: 10.1038/s41589-019-0277-7. Epub 2019 May 13.

Authors

Affiliations

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.

PMID: 31086327
DOI: 10.1038/s41589-019-0277-7

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.

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Comment in

Walking over the inflammasome.
Gorka O, Neuwirt E, Groß O. Gorka O, et al. Nat Chem Biol. 2019 Jun;15(6):552-553. doi: 10.1038/s41589-019-0292-8. Nat Chem Biol. 2019. PMID: 31086328 No abstract available.

References

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1. Broderick, L. et al. Annu. Rev. Pathol. 10, 395–424 (2015). - DOI

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

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

Authors

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