Nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing protein 3 (NLRP3) (NLRP3)

The Nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing protein 3 (NLRP3) is a critical intracellular sensor of the innate immune system that detects a wide range of pathogen-associated and danger-associated molecular patterns. Upon activation, NLRP3 undergoes a conformational change and oligomerizes to form the NLRP3 inflammasome, a multiprotein complex that activates caspase-1. This activation leads to the maturation and secretion of pro-inflammatory cytokines, specifically interleukin-1β (IL-1β) and interleukin-18 (IL-18), and can trigger a form of programmed cell death known as pyroptosis. The central NACHT domain, which contains the nucleotide-binding domain (NBD), is essential for the protein's ATPase activity, which drives the oligomerization process. Dysregulation or constitutive activation of NLRP3 is implicated in numerous inflammatory and autoimmune conditions, including cryopyrin-associated periodic syndromes (CAPS), gout, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Consequently, the NBD of NLRP3 has become a major therapeutic target for small-molecule inhibitors, such as MCC950 and dapansutrile, which aim to block ATPase activity and prevent the assembly of the inflammatory complex. While the term "Nucleotide Binding Domain of the studied protein" is generic and could technically refer to other proteins like ABC transporters or Hsp70, NLRP3 is currently the most prominent therapeutic target where the NBD is the specific site of action for a large class of experimental drugs.

Other names

CryopyrinCIAS1PYPAF1NALP3Caspase recruitment domain-containing protein 7NACHT, LRR and PYD domains-containing protein 3

Inhibition of NLRP3 ATPase activity and inflammasome assembly