MCC950 closes the active conformation of NLRP3 to an inactive state

Nat Chem Biol. 2019 Jun;15(6):560-564. doi: 10.1038/s41589-019-0278-6. Epub 2019 May 13.

Abstract

NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Furans
  • HEK293 Cells
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Indenes
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Protein Conformation
  • Sulfonamides
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • Indenes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Sulfonamides
  • Sulfones
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide