9mie
Human NLRP3 complex with compound 2 in the closed hexamer
Structural highlights
DiseaseNLRP3_HUMAN CINCA syndrome with NLRP3 mutations;Familial cold urticaria;Muckle-Wells syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionNLRP3_HUMAN As the sensor component of the NLRP3 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1 (and possibly CASP4 and CASP5). Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP3 inflammasome is also required for HMGB1 secretion (PubMed:22801494). The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death. Under resting conditions, NLRP3 is autoinhibited. NLRP3 activation stimuli include extracellular ATP, reactive oxygen species, K(+) efflux, crystals of monosodium urate or cholesterol, beta-amyloid fibers, environmental or industrial particles and nanoparticles, etc. However, it is unclear what constitutes the direct NLRP3 activator. Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity).[UniProtKB:Q8R4B8][1] [2] Publication Abstract from PubMedNLRP3 is a danger sensor protein responsible for inflammasome activation. This leads to pro-inflammatory cytokines release, like IL-1beta, and pyroptosis, a regulated cell death. Mounting evidence associates excessive NLRP3 activation to neurodegenerative conditions, such as Alzheimer's and Parkinson's diseases. Thus, NLRP3 inhibitors could potentially provide therapeutic benefit for these disorders. We describe here the evolution of inhibitors relying on a pyridazine-based motif for their key interactions with NLRP3. A Cryo-EM structure helped optimizing protein-ligand complementarity. Subsequently, conformational NMR studies pointed the efforts toward 5,6-bicyclic cores that allowed a balance between brain penetration and undesirable properties, such as hERG inhibition. The effort culminated in compound 19, which showed moderate (mouse) to good (rat) brain penetration and was active at low dose in an LPS challenge model. Importantly, an earlier compound was active in a central neuroinflammation model providing a valuable proof of concept for NLRP3 inhibition. Discovery of Potent and Brain-Penetrant Bicyclic NLRP3 Inhibitors with Peripheral and Central In Vivo Activity.,Mammoliti O, Carbajo R, Perez-Benito L, Yu X, Prieri MLC, Bontempi L, Embrechts S, Paesmans I, Bassi M, Bhattacharya A, Canellas S, De Hoog S, Demin S, Gijsen HJM, Hache G, Jacobs T, Jerhaoui S, Leenaerts J, Lutter FH, Mahieu M, Matico R, Miller R, Oehlrich D, Perrier M, Ryabchuk P, Schepens W, Sharma S, Somers M, Suarez J, Surkyn M, Van Opdenbosch N, Verhulst T, Bottelbergs A J Med Chem. 2025 Feb 11. doi: 10.1021/acs.jmedchem.4c03108. PMID:39932543[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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