View source for 9sfg


==Crystal structure of NLRP3 in complex with inhibitor NP3-742==
<StructureSection load='9sfg' size='340' side='right'caption='[[9sfg]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9sfg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9SFG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9SFG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JNK:5-methyl-~{N}-[(3~{R})-1-methylpiperidin-3-yl]-6-(2-methyl-1~{H}-pyrrolo[2,3-b]pyridin-6-yl)pyridazin-3-amine'>A1JNK</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9sfg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9sfg OCA], [https://pdbe.org/9sfg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9sfg RCSB], [https://www.ebi.ac.uk/pdbsum/9sfg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9sfg ProSAT]</span></td></tr>
</table>
== 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
NLRP3 is a molecular sensor present in innate immune cells which recognizes a variety of danger signals such as MSU, ATP, or Abeta. Upon activation, it seeds a protein complex termed the inflammasome, which leads to secretion of the proinflammatory cytokines IL-1beta and IL-18 and initiates pyroptotic cell death. NLRP3 inflammasome activation has been associated with a wide range of diseases including atherosclerosis, gout, and cancer. In this publication, we describe the replacement of the phenol moiety with indoles in the recently described pyridazine scaffold. This replacement required a shift of the hydrogen bond donor from the "ortho" to the "meta" position, relative to the pyridazine ring. Initial indole analog 7 demonstrated a robust in vivo IL-1beta inhibition, but also a significant hERG inhibition. Decreasing lipophilicity led to the discovery of NP3-742, demonstrating a favorable overall profile including diminished hERG inhibition and in vivo efficacy in a mouse peritonitis model.

Discovery of NP3-742: A Structurally Diverse NLRP3 Inhibitor Identified through an Unusual Phenol Replacement.,Velcicky J, Langlois JB, Wright M, Janser P, Angst D, Arnold C, Beltz K, Brenneisen S, Dubois C, Dawson J, Fischer C, Gommermann N, Heizmann A, Ilic S, Machauer R, Maschlej M, Monnerat S, Pflieger D, Ristov J, Rubert J, Schwalm G, Smith DR, Srinivas H, Steiner R, Stojanovic A, Troxler T, Unterreiner A, Vangrevelinghe E, von Burg N, Wunderlich J, Farady CJ, Mackay A J Med Chem. 2025 Oct 15. doi: 10.1021/acs.jmedchem.5c02412. PMID:41091523<ref>PMID:41091523</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9sfg" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Srinivas H]]