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TLR4

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1754

Nomenclature: TLR4

Family: Toll-like receptor family

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 839 9q33.1 TLR4 toll like receptor 4
Mouse 1 835 4 34.66 cM Tlr4 toll-like receptor 4
Rat 1 835 5q24 Tlr4 toll-like receptor 4
Previous and Unofficial Names Click here for help
ARMD10 | CD284 | toll-like receptor 4 | TOLL | TLR-4
Database Links Click here for help
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
Pharos
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of mouse TLR4/MD-2/neoseptin-3 complex.
PDB Id:  5IJC
Ligand:  neoceptin-3
Resolution:  2.57Å
Species:  Mouse
References:  18

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

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GSK1795091 Small molecule or natural product Hs Agonist 9.8 pEC50 4
pEC50 9.8 (EC50 1.7x10-10 M) [4]
Description: Determined by measuring induction of TNFα production in primary human monocytes.
paclitaxel Small molecule or natural product Approved drug Ligand has a PDB structure Mm Agonist - - 11
[11]
defoslimod Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Mm Agonist - - 7
[7]
neoceptin-3 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist - - 18
[18]
CRX-555 Small molecule or natural product Immunopharmacology Ligand Hs Partial agonist - - 17
[17]
View species-specific agonist tables
Agonist Comments
Chan et al. (2013) describe a SAR study to identify TLR4 pathway activators [6].
A range of structurally diverse, natural and synthetic TLR4 activators and inhibitors are reviewed by Peri and Calabrese (2014) [14].
Revelation Biosciences are developing a synthetic version of monophosphoryl lipid A as a TLR4 activator, to stimulate Type I and Type II interferons as a mechanism to combat early SARS-CoV-2 infection. Their candidate REVTx-99 is delivered intranasally, and is expected to begin evaluation in a Phase 1 study (in Australia) in the 4th quarter of 2020,
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
resatorvid Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Antagonist - - 8
[8]
Antagonist Comments
A range of structurally diverse, natural and synthetic TLR4 activators and inhibitors are reviewed by Peri and Calabrese (2014) [14].
Immunopharmacology Comments
TLR4 selectively responds to bacterial endotoxin, Gram-negative bacterial lipopolysaccharides (LPS), and lipooligosaccharides (LOS) [5,15], and a range of substances from viruses, fungi, and mycoplasma [9]. TLR4 also responds to danger (or damage) associated molecular patterns (DAMPs) which include endogenous substances released as a consequence of injury and inflammation [2,12].
TLR4 is unique among the TLRs in triggering two distinct signal/transduction pathways: the myeloid differentiating primary response gene 88 (MyD88) dependent pathway and the MyD88-independent pathway based on the TRIF and TRAM effectors. LPS engagement leads to the formation of activated TLR4 which is a protein complex with structure (LPS.MD-2.TLR4)2 [10,13,16].
TLR4 is a therapeutic molecular target. Many lipid A (a component of LPS) analogues have been used to study the structure and function of TLR4 and the information gained has been used to rationally design new therapeutic compounds. A few TLR4 inhibitors (e.g. eritoran [3] and resatorvid) have failed in Phase III clinical trials despite exhibiting preclinical efficacy. So, the search for TLR4 modulators (either direct antagonists or alternatively, compounds which disrupt MD-2-TLR4 interaction e.g. L6H21) with potential to treat a wide range of pathologies, not only acute infection (sepsis) but also inflammatory and autoimmune disorders and some tumours, is ongoing [14].
Nature Reviews Drug Discovery immuno-oncology review [1].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 16 GO processes
GO:0001774 microglial cell activation ISO
GO:0001875 lipopolysaccharide immune receptor activity IDA
GO:0002218 activation of innate immune response IMP
GO:0002758 innate immune response-activating signal transduction ISO
GO:0006909 phagocytosis IDA
GO:0006954 inflammatory response IBA
GO:0042116 macrophage activation IMP
GO:0043032 positive regulation of macrophage activation ISS
GO:0045087 innate immune response TAS
GO:0045576 mast cell activation NAS
GO:0050727 regulation of inflammatory response IMP
GO:0050729 positive regulation of inflammatory response IC
GO:0071346 cellular response to interferon-gamma IDA
GO:1900017 positive regulation of cytokine production involved in inflammatory response ISS
click arrow to show/hide IEA associations
GO:0002322 B cell proliferation involved in immune response IEA
GO:0002537 nitric oxide production involved in inflammatory response IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0016064 immunoglobulin mediated immune response IEP
GO:0042088 T-helper 1 type immune response NAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 4 GO processes
GO:0016064 immunoglobulin mediated immune response IEP
GO:0042088 T-helper 1 type immune response NAS
click arrow to show/hide IEA associations
GO:0002322 B cell proliferation involved in immune response IEA
GO:0030890 positive regulation of B cell proliferation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 12 GO processes
GO:0001875 lipopolysaccharide immune receptor activity IDA
GO:0002218 activation of innate immune response IMP
GO:0002758 innate immune response-activating signal transduction ISO
GO:0043032 positive regulation of macrophage activation ISS
GO:0045671 negative regulation of osteoclast differentiation NAS
GO:0050671 positive regulation of lymphocyte proliferation IMP
GO:0050727 regulation of inflammatory response IMP
GO:0050729 positive regulation of inflammatory response IC
GO:1900017 positive regulation of cytokine production involved in inflammatory response ISS
click arrow to show/hide IEA associations
GO:0002730 regulation of dendritic cell cytokine production IEA
GO:0030890 positive regulation of B cell proliferation IEA
GO:0060907 positive regulation of macrophage cytokine production IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes
GO:0045671 negative regulation of osteoclast differentiation NAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 24 GO processes
GO:0032611 interleukin-1 beta production ISS
GO:0032689 negative regulation of interferon-gamma production ISS
GO:0032700 negative regulation of interleukin-17 production ISS
GO:0032707 negative regulation of interleukin-23 production ISS
GO:0032715 negative regulation of interleukin-6 production ISS
GO:0032720 negative regulation of tumor necrosis factor production ISS
GO:0032722 positive regulation of chemokine production IDA
GO:0032727 positive regulation of interferon-alpha production ISS
GO:0032728 positive regulation of interferon-beta production ISS
GO:0032729 positive regulation of interferon-gamma production ISS
GO:0032731 positive regulation of interleukin-1 beta production IDA
GO:0032732 positive regulation of interleukin-1 production ISS
GO:0032733 positive regulation of interleukin-10 production ISS
GO:0032735 positive regulation of interleukin-12 production ISS
GO:0032755 positive regulation of interleukin-6 production IDA
GO:0032757 positive regulation of interleukin-8 production IDA
GO:0032760 positive regulation of tumor necrosis factor production ISS
GO:0071346 cellular response to interferon-gamma IDA
GO:1900017 positive regulation of cytokine production involved in inflammatory response ISS
GO:1903974 positive regulation of cellular response to macrophage colony-stimulating factor stimulus IDA
GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production IMP
click arrow to show/hide IEA associations
GO:0002730 regulation of dendritic cell cytokine production IEA
GO:0032609 interferon-gamma production IEA
GO:0060907 positive regulation of macrophage cytokine production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes
GO:0032722 positive regulation of chemokine production IDA
GO:2000343 positive regulation of chemokine (C-X-C motif) ligand 2 production IMP
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 9 GO processes
GO:0001774 microglial cell activation ISO
GO:0001875 lipopolysaccharide immune receptor activity IDA
GO:0002758 innate immune response-activating signal transduction ISO
GO:0042116 macrophage activation IMP
GO:0043032 positive regulation of macrophage activation ISS
GO:0045576 mast cell activation NAS
GO:0050671 positive regulation of lymphocyte proliferation IMP
click arrow to show/hide IEA associations
GO:0002322 B cell proliferation involved in immune response IEA
GO:0030890 positive regulation of B cell proliferation IEA
Physiological Functions Comments
Involved in the detection of lipopolysaccharide; pro-inflammatory.
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Asthma, susceptibility to
Disease Ontology: DOID:2841
OMIM: 600807
Disease:  Atherosclerosis susceptibility
Disease Ontology: DOID:1936
OMIM: 108725
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
Disease:  Crohn's disease
Synonyms: Crohn disease [Disease Ontology: DOID:8778]
Inflammatory bowel disease 1; IBD1 [OMIM: 266600]
Disease Ontology: DOID:8778
OMIM: 266600
Orphanet: ORPHA206
Disease:  Endotoxin hyporesponsiveness
OMIM: 603030
Disease:  Gastritis
Disease Ontology: DOID:4029
Disease:  Gram negative infection
Disease:  Macular degeneration, age-related, 10; ARMD10
Synonyms: Age related macular degeneration [Disease Ontology: DOID:10871] [Orphanet: ORPHA279]
Disease Ontology: DOID:10871
OMIM: 611488
Orphanet: ORPHA279
Disease:  Preterm birth
Synonyms: Premature labor [Disease Ontology: DOID:10875]
Disease Ontology: DOID:10875
Disease:  Sepsis
Synonyms: Septicemia
Disease:  Ulcerative colitis
Synonyms: Inflammatory bowel disease 1; IBD1 [OMIM: 266600]
Disease Ontology: DOID:8577
OMIM: 266600
Orphanet: ORPHA771
General Comments

References

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1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Akira S, Takeda K. (2004) Toll-like receptor signalling. Nat Rev Immunol, 4 (7): 499-511. [PMID:15229469]

3. Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ. (2011) Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Expert Opin Drug Metab Toxicol, 7 (4): 479-94. [PMID:21323610]

4. Bazin HG, Murray TJ, Bowen WS, Mozaffarian A, Fling SP, Bess LS, Livesay MT, Arnold JS, Johnson CL, Ryter KT et al.. (2008) The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics. Bioorg Med Chem Lett, 18 (20): 5350-4. [PMID:18835160]

5. Beutler B, Du X, Poltorak A. (2001) Identification of Toll-like receptor 4 (Tlr4) as the sole conduit for LPS signal transduction: genetic and evolutionary studies. J Endotoxin Res, 7 (4): 277-80. [PMID:11717581]

6. Chan M, Hayashi T, Mathewson RD, Nour A, Hayashi Y, Yao S, Tawatao RI, Crain B, Tsigelny IF, Kouznetsova VL et al.. (2013) Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands. J Med Chem, 56 (11): 4206-23. [PMID:23656327]

7. Garay RP, Viens P, Bauer J, Normier G, Bardou M, Jeannin JF, Chiavaroli C. (2007) Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur J Pharmacol, 563 (1-3): 1-17. [PMID:17383632]

8. Ii M, Matsunaga N, Hazeki K, Nakamura K, Takashima K, Seya T, Hazeki O, Kitazaki T, Iizawa Y. (2006) A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. Mol Pharmacol, 69 (4): 1288-95. [PMID:16373689]

9. Jeong E, Lee JY. (2011) Intrinsic and extrinsic regulation of innate immune receptors. Yonsei Med J, 52 (3): 379-92. [PMID:21488180]

10. Jerala R. (2007) Structural biology of the LPS recognition. Int J Med Microbiol, 297 (5): 353-63. [PMID:17481951]

11. Kawasaki K, Akashi S, Shimazu R, Yoshida T, Miyake K, Nishijima M. (2000) Mouse toll-like receptor 4.MD-2 complex mediates lipopolysaccharide-mimetic signal transduction by Taxol. J Biol Chem, 275 (4): 2251-4. [PMID:10644670]

12. Lucas K, Maes M. (2013) Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol, 48 (1): 190-204. [PMID:23436141]

13. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature, 458 (7242): 1191-5. [PMID:19252480]

14. Peri F, Calabrese V. (2014) Toll-like receptor 4 (TLR4) modulation by synthetic and natural compounds: an update. J Med Chem, 57 (9): 3612-22. [PMID:24188011]

15. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C et al.. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science, 282 (5396): 2085-8. [PMID:9851930]

16. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M. (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med, 189 (11): 1777-82. [PMID:10359581]

17. Stöver AG, Da Silva Correia J, Evans JT, Cluff CW, Elliott MW, Jeffery EW, Johnson DA, Lacy MJ, Baldridge JR, Probst P et al.. (2004) Structure-activity relationship of synthetic toll-like receptor 4 agonists. J Biol Chem, 279 (6): 4440-9. [PMID:14570885]

18. Wang Y, Su L, Morin MD, Jones BT, Whitby LR, Surakattula MM, Huang H, Shi H, Choi JH, Wang KW et al.. (2016) TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. Proc Natl Acad Sci USA, 113 (7): E884-93. [PMID:26831104]

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