7alv
From Proteopedia
Crystal Structure of NLRP3 NACHT domain in complex with a potent inhibitor
Structural highlights
Disease[NLRP3_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. Function[NLRP3_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 PubMedThe NLRP3 inflammasome assembles in response to a variety of pathogenic and sterile danger signals, resulting in the production of interleukin-1beta and interleukin-18. NLRP3 is a key component of the innate immune system and has been implicated as a driver of a number of acute and chronic diseases. We report the 2.8 A crystal structure of the NLRP3 NACHT domain in complex with an inhibitor. The structure defines a binding pocket formed by the four subdomains of the NACHT domain, and shows the inhibitor acts as an intramolecular glue, which locks the protein in an inactive conformation. It provides further molecular insight into our understanding of NLRP3 activation, helps to detail the residues involved in subdomain coordination within the NLRP3 NACHT domain, and gives molecular insights into how gain-of-function mutations de-stabilize the inactive conformation of NLRP3. Finally, it suggests stabilizing the auto-inhibited form of the NACHT domain is an effective way to inhibit NLRP3, and will aid the structure-based development of NLRP3 inhibitors for a range of inflammatory diseases. Crystal structure of NLRP3 NACHT domain with an inhibitor defines mechanism of inflammasome inhibition.,Dekker C, Mattes H, Wright M, Boettcher A, Hinniger A, Hughes N, Kapps-Fouthier S, Eder J, Erbel P, Stiefl N, Mackay A, Farady CJ J Mol Biol. 2021 Oct 20:167309. doi: 10.1016/j.jmb.2021.167309. PMID:34687713[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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