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

  • Nat Chem Biol. 2019 Jun;15(6):556-559. doi: 10.1038/s41589-019-0277-7.
Rebecca C Coll  1 ,  James R Hill  2 ,  Christopher J Day  3 ,  Alina Zamoshnikova  2  4 ,  Dave Boucher  2  5 ,  Nicholas L Massey  2 ,  Jessica L Chitty  6  7  8 ,  James A Fraser  6 ,  Michael P Jennings  3 ,  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. [email protected].
  • 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. [email protected].
  • 10. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. [email protected].
  • 11. Institute for Molecular Bioscience and IMB Centre for Inflammation and Disease Research, The University of Queensland, St Lucia, Queensland, Australia. [email protected].
  • 12. Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia. [email protected].
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.