MCC950 closes the active conformation of NLRP3 to an inactive state.

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.

• Authors: Ana Tapia-Abellán, Diego Angosto-Bazarra, Helios Martínez-Banaclocha, Carlos de Torre-Minguela, Jose P Cerón-Carrasco, Horacio Pérez-Sánchez, Juan I Arostegui, Pablo Pelegrin
• Journal: Nature chemical biology (Nat Chem Biol) Vol. 15 Issue 6 Pg. 560-564 (06 2019) ISSN: 1552-4469 [Electronic] United States
• PMID: 31086329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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