TLR4 | Toll-like receptor family | IUPHAR/BPS Guide to PHARMACOLOGY

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TLR4

target has curated data in GtoImmuPdb

Target id: 1754

Nomenclature: TLR4

Family: Toll-like receptor family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 816 9q33.1 TLR4 toll like receptor 4
Mouse - 810 4 34.66 cM Tlr4 toll-like receptor 4
Rat - 810 5q24 Tlr4 toll-like receptor 4
Previous and Unofficial Names
ARMD10 | CD284 | toll-like receptor 4 | TLR-4 | TOLL
Database Links
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
UniProtKB
Wikipedia
Selected 3D Structures
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:  17

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
paclitaxel Mm Agonist - - 10
[10]
defoslimod Mm Agonist - - 6
[6]
neoceptin-3 Hs Agonist - - 17
[17]
CRX-555 Hs Partial agonist - - 16
[16]
View species-specific agonist tables
Agonist Comments
Chan et al. (2013) describe a SAR study to identify TLR4 pathway activators [5].
A range of structurally diverse, natural and synthetic TLR4 activators and inhibitors are reviewed by Peri and Calabrese (2014) [13].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
resatorvid Hs Antagonist - - 7
[7]
Antagonist Comments
A range of structurally diverse, natural and synthetic TLR4 activators and inhibitors are reviewed by Peri and Calabrese (2014) [13].
Immunopharmacology Comments
TLR4 selectively responds to bacterial endotoxin, Gram-negative bacterial lipopolysaccharides (LPS), and lipooligosaccharides (LOS) [4,14], and a range of substances from viruses, fungi, and mycoplasma [8]. TLR4 also responds to danger (or damage) associated molecular patterns (DAMPs) which include endogenous substances released as a consequence of injury and inflammation [2,11].
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 [9,12,15].
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 [13].
Nature Reviews Drug Discovery immuno-oncology review [1].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 19 GO processes
GO:0001875 lipopolysaccharide receptor activity IDA
GO:0002224 toll-like receptor signaling pathway IBA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway ISS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0006909 phagocytosis IDA
GO:0006954 inflammatory response IBA
GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway TAS
GO:0034142 toll-like receptor 4 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway ISS
GO:0042116 macrophage activation IMP
GO:0043032 positive regulation of macrophage activation ISS
GO:0045087 innate immune response TAS
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
GO:0070430 positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway IEA
GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0042088 T-helper 1 type immune response NAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 3 GO processes
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 16 GO processes
GO:0001875 lipopolysaccharide receptor activity IDA
GO:0002224 toll-like receptor signaling pathway IBA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway ISS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway TAS
GO:0034142 toll-like receptor 4 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway ISS
GO:0043032 positive regulation of macrophage activation ISS
GO:0045671 negative regulation of osteoclast differentiation NAS
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
GO:0070430 positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway IEA
GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway 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 27 GO processes
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: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:0042535 positive regulation of tumor necrosis factor biosynthetic process IDA
GO:0045084 positive regulation of interleukin-12 biosynthetic process IDA
GO:0045416 positive regulation of interleukin-8 biosynthetic process IDA
GO:0050702 interleukin-1 beta secretion ISS
GO:0050718 positive regulation of interleukin-1 beta secretion IDA
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
click arrow to show/hide IEA associations
GO:0002730 regulation of dendritic cell cytokine production IEA
GO:0032609 interferon-gamma production IEA
GO:0045359 positive regulation of interferon-beta biosynthetic process IEA
GO:0060907 positive regulation of macrophage cytokine production IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0032722 positive regulation of chemokine production IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 13 GO processes
GO:0001875 lipopolysaccharide receptor activity IDA
GO:0002224 toll-like receptor signaling pathway IBA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway ISS
GO:0002756 MyD88-independent toll-like receptor signaling pathway TAS
GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway TAS
GO:0034142 toll-like receptor 4 signaling pathway TAS
GO:0035666 TRIF-dependent toll-like receptor signaling pathway ISS
GO:0042116 macrophage activation IMP
GO:0043032 positive regulation of macrophage activation ISS
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
GO:0070430 positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway IEA
GO:0070434 positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway IEA
Physiological Functions Comments
Involved in the detection of lipopolysaccharide; pro-inflammatory.
Clinically-Relevant Mutations and Pathophysiology
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. 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]

5. 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]

6. 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]

7. 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]

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

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

10. 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]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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. U.S.A., 113 (7): E884-93. [PMID:26831104]

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