7pzc

<table><tr><td colspan='2'>[[7pzc]] is a 10 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PZC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PZC FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8GI:1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(2-oxidanylpropan-2-yl)furan-2-yl]sulfonyl-urea'>8GI</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene></td></tr>

== Disease ==

[[https://www.uniprot.org/uniprot/NLRP3_HUMAN 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 ==

[[https://www.uniprot.org/uniprot/NLRP3_HUMAN 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]<ref>PMID:22801494</ref> <ref>PMID:23305783</ref>

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== Publication Abstract from PubMed ==

NLRP3 is an intracellular sensor protein whose activation by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis(1,2). The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood(2,3). Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950)(4). Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined LRR domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One PYD dimer is additionally formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRRs are mediated by an acidic loop extending from an LRR transition segment. Binding of CRID3 significantly stabilizes the NACHT and LRR domains relative to each other, allowing structural resolution of 3.8-4.2 A. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginines, explaining the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this lead therapeutic, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization are within reach.

Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3.,Hochheiser IV, Pilsl M, Hagelueken G, Moecking J, Marleaux M, Brinkschulte R, Latz E, Engel C, Geyer M Nature. 2022 Feb 3. pii: 10.1038/s41586-022-04467-w. doi:, 10.1038/s41586-022-04467-w. PMID:35114687<ref>PMID:35114687</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

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== References ==

<references/>

[[Category: Engel, C]]

[[Category: Geyer, M]]

[[Category: Hagelueken, G]]

[[Category: Hochheiser, I V]]

[[Category: Pilsl, M]]

[[Category: Nod-like receptor]]