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.
Ana Tapia-Abellán  1 ,  Diego Angosto-Bazarra  1 ,  Helios Martínez-Banaclocha  1 ,  Carlos de Torre-Minguela  1 ,  Jose P Cerón-Carrasco  2 ,  Horacio Pérez-Sánchez  2 ,  Juan I Arostegui  3 ,  Pablo Pelegrin  4
Affiliations
  • 1. Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain.
  • 2. Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica de Murcia (UCAM), Murcia, Spain.
  • 3. Department of Immunology, Hospital Clinic-IDIBAPS, Barcelona, Spain.
  • 4. Biomedical Research Institute of Murcia (IMIB-Arrixaca), University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain. [email protected].
PMID: 31086329 DOI: 10.1038/s41589-019-0278-6
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.