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NLRP3

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 1770

Nomenclature: NLRP3

Family: NOD-like receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1036 1q44 NLRP3 NLR family pyrin domain containing 3
Mouse - 1033 11 B1.3 Nlrp3 NLR family, pyrin domain containing 3
Rat - - 10q22 Nlrp3 NLR family, pyrin domain containing 3
Previous and Unofficial Names Click here for help
AVP | C1orf7 | CIAS1 | NALP3 | AGTAVPRL | CLR1.1 | FCAS | FCU | MWS | AII | cold autoinflammatory syndrome 1 | Cryopyrin | NACHT, LRR and PYD domains-containing protein 3 | NLR family, pyrin domain containing 3 | PYPAF1 | NLR family
Database Links Click here for help
CATH/Gene3D 3.80.10.10
ChEMBL Target CHEMBL1741208 (Hs), CHEMBL3779755 (Mm)
Ensembl Gene ENSG00000162711 (Hs), ENSMUSG00000032691 (Mm), ENSRNOG00000003170 (Rn)
Entrez Gene 114548 (Hs), 216799 (Mm), 287362 (Rn)
Human Protein Atlas ENSG00000162711 (Hs)
KEGG Gene hsa:114548 (Hs), mmu:216799 (Mm), rno:287362 (Rn)
OMIM 606416 (Hs)
Pharos Q96P20 (Hs)
UniProtKB Q96P20 (Hs), Q8R4B8 (Mm)
Wikipedia NLRP3 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CY-09 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition 6.3 pKd 6
⤷ pKd 6.3 (Kd 5x10-7 M) [6]
Description: MST assay for the affinity between CY-09 and purified GFP-NLRP3 protein.
MCC950 Small molecule or natural product Immunopharmacology Ligand Hs Inhibition >8.0 pIC50 2
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [2]
dapansutrile Small molecule or natural product Immunopharmacology Ligand Hs Inhibition - - 9
⤷ [9]
Description: As assessed by inhibition of recombinant NLRP3 ATPase activity by dapansutrile.
Immunopharmacology Comments
NLRP3 is a component of the NLRP3 inflammasome, a protein complex which activates caspase-1, and plays an important role in the regulation of inflammation and apoptosis (pyroptosis). Drug-like NLRP3 inhibitors are under investigation as novel therapeutics for the treatment of autoinflammatory diseases and neuroinflammation, as an alternative to anti-IL-1 therapies such as rilonacept, anakinra and canakinumab [1,7]. The potential of pharmacological modulation of the NLRP3 inflammasome as a mechanism to treat inflammatory diseases is reviewed by Mangan et al. (2018) [8].

NLRP3 inflammasome activation by tau in microglia has been demonstrated to drive amyloid-β pathology, including neuroinflammation and formation of neurofibrillary tangles [5].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 8 GO processes
GO:0002674 negative regulation of acute inflammatory response IMP
GO:0006954 inflammatory response IMP
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:0050727 regulation of inflammatory response IMP
GO:0050728 negative regulation of inflammatory response IMP
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
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GO:0045087 innate immune response IEA
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 7 GO processes
GO:0002674 negative regulation of acute inflammatory response IMP
GO:0002830 positive regulation of type 2 immune response ISS
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
GO:0050727 regulation of inflammatory response IMP
GO:0050728 negative regulation of inflammatory response IMP
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 2 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 7 GO processes
GO:0032753 positive regulation of interleukin-4 production ISS
GO:2000553 positive regulation of T-helper 2 cell cytokine production ISS
click arrow to show/hide IEA associations
GO:0002374 cytokine secretion involved in immune response IEA
GO:0032611 interleukin-1 beta production IEA
GO:0032621 interleukin-18 production IEA
GO:0032736 positive regulation of interleukin-13 production IEA
GO:0032754 positive regulation of interleukin-5 production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0045630 positive regulation of T-helper 2 cell differentiation ISS
click arrow to show/hide IEA associations
GO:2000321 positive regulation of T-helper 17 cell differentiation IEA
Physiological Functions Comments
Involved in inflammasome formation and caspase-1 activation.
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Alzheimer disease
Synonyms: Alzheimer's disease [Disease Ontology: DOID:10652]
Disease Ontology: DOID:10652
OMIM: 104300
Disease:  Atherosclerosis susceptibility
Disease Ontology: DOID:1936
OMIM: 108725
Disease:  CINCA syndrome
Synonyms: Chronic infantile neurological cutaneous articular syndrome
OMIM: 607115
Orphanet: ORPHA1451
Disease:  Diabetes mellitus, noninsulin-dependent; NIDDM
Synonyms: Diabetes mellitus, Type II; T2D [OMIM: 125853]
Maturity onset diabetes
Type 2 diabetes mellitus [Disease Ontology: DOID:9352]
Disease Ontology: DOID:9352
OMIM: 125853
Disease:  Familial cold autoinflammatory syndrome 1; FCAS1
Synonyms: Familial cold urticaria [Orphanet: ORPHA47045]
OMIM: 120100
Orphanet: ORPHA47045
Disease:  Gout
Disease Ontology: DOID:13189
Disease:  Inflammatory bowel disease
Synonyms: Inflammatory bowel disease [Disease Ontology: DOID:0050589]
Disease Ontology: DOID:0050589
OMIM: 266600
Disease:  Muckle-Wells syndrome
Description: Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis.
Synonyms: CAPS2
cryopyrin-associated periodic syndrome 2
MWS
urticaria-deafness-amyloidosis syndrome
OMIM: 191900
Orphanet: ORPHA575
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human R260W 778C>T 3
Missense Human A352V 1055C>T 4
Missense Human G569R 1705G>C 3
Biologically Significant Variants Click here for help
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  C/T
Amino acids:  352
SNP accession:  rs121908149
References:  4
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  G/C
Amino acids:  569
SNP accession:  rs121908151
References:  3
Type:  Naturally occurring mutation
Species:  Human
Nucleotide change:  C/T
Amino acids:  260
SNP accession:  rs121908150
References:  3

References

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1. Baldwin AG, Brough D, Freeman S. (2016) Inhibiting the Inflammasome: A Chemical Perspective. J. Med. Chem., 59 (5): 1691-710. [PMID:26422006]

2. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, Vetter I, Dungan LS, Monks BG, Stutz A et al.. (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med., 21 (3): 248-55. [PMID:25686105]

3. Dodé C, Le Dû N, Cuisset L, Letourneur F, Berthelot JM, Vaudour G, Meyrier A, Watts RA, Scott DG, Nicholls A et al.. (2002) New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am. J. Hum. Genet., 70 (6): 1498-506. [PMID:11992256]

4. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet., 29 (3): 301-5. [PMID:11687797]

5. Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D et al.. (2019) NLRP3 inflammasome activation drives tau pathology. Nature, 575 (7784): 669-673. [PMID:31748742]

6. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q et al.. (2017) Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J. Exp. Med., 214 (11): 3219-3238. [PMID:29021150]

7. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 17 (9): 688. [PMID:30116046]

8. Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. (2018) Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov, 17 (8): 588-606. [PMID:30026524]

9. Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, Carta S, Tengesdal I, Nemkov T, D'Alessandro A et al.. (2018) OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc. Natl. Acad. Sci. U.S.A., 115 (7): E1530-E1539. [PMID:29378952]

Contributors

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