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PDBsum entry 2z64

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protein ligands Protein-protein interface(s) links
Immune system PDB id
2z64
Jmol
Contents
Protein chains
599 a.a. *
135 a.a. *
Ligands
NAG-NAG
NAG-NAG-BMA ×2
NAG ×3
NDG ×6
NAG-FUL-NAG-BMA
Waters ×154
* Residue conservation analysis
PDB id:
2z64
Name: Immune system
Title: Crystal structure of mouse tlr4 and mouse md-2 complex
Structure: Toll-like receptor 4. Chain: a. Fragment: tlr4, unp residues 27-625. Synonym: cd284 antigen. Engineered: yes. Lymphocyte antigen 96. Chain: c. Fragment: md-2, unp residues 21-160. Synonym: md-2 protein, esop-1.
Source: Mus musculus. House mouse. Organism_taxid: 10090. Gene: tlr4. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: md2.
Resolution:
2.84Å     R-factor:   0.244     R-free:   0.290
Authors: J.-O.Lee,H.M.Kim,B.S.Park
Key ref:
H.M.Kim et al. (2007). Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell, 130, 906-917. PubMed id: 17803912 DOI: 10.1016/j.cell.2007.08.002
Date:
22-Jul-07     Release date:   18-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9QUK6  (TLR4_MOUSE) -  Toll-like receptor 4
Seq:
Struc:
 
Seq:
Struc:
835 a.a.
599 a.a.
Protein chain
Pfam   ArchSchema ?
Q9JHF9  (LY96_MOUSE) -  Lymphocyte antigen 96
Seq:
Struc:
160 a.a.
135 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   4 terms 
  Biological process     immune system process   12 terms 
  Biochemical function     protein binding     3 terms  

 

 
DOI no: 10.1016/j.cell.2007.08.002 Cell 130:906-917 (2007)
PubMed id: 17803912  
 
 
Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.
H.M.Kim, B.S.Park, J.I.Kim, S.E.Kim, J.Lee, S.C.Oh, P.Enkhbayar, N.Matsushima, H.Lee, O.J.Yoo, J.O.Lee.
 
  ABSTRACT  
 
TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overall Structure of the Mouse TLR4-MD-2 Complex
(A–C) Three views of the mouse TLR4-MD-2 complex are shown in the diagrams. The N-terminal, central, and C-terminal domains of TLR4 are colored in blue, cyan, and green, respectively. The beta strands of MD-2 are shown in pink and red, and the LRR modules of TLR4 are numbered.
(D) Closeup view of mouse MD-2. Disulfide bridges are shown in yellow and cysteines are labeled. Cys133 is not involved in the disulfide bridge formation. The orientation of this view is the same as for (C).
Figure 4.
Figure 4. Assembly of the Full-Length Ectodomain of Human TLR4
Structures of the three human TLR4-VLRB.61 hybrids. TLR4 fragments are colored blue and VLRB.61 fragments gray. The full-length ectodomain of human TLR4 was assembled after superimposition of the overlapping regions of the TV8 and VT3 hybrids. The disulfide bridges are represented in orange.
 
  The above figures are reprinted by permission from Cell Press: Cell (2007, 130, 906-917) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity.
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21481769 I.Botos, D.M.Segal, and D.R.Davies (2011).
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21239391 M.Alcaide, and S.V.Edwards (2011).
Molecular evolution of the toll-like receptor multigene family in birds.
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21857663 S.I.Yoon, M.Hong, and I.A.Wilson (2011).
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PDB code: 3rg1
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Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli.
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PDB code: 3my2
20351099 A.van Mourik, L.Steeghs, J.van Laar, H.D.Meiring, H.J.Hamstra, J.P.van Putten, and M.M.Wösten (2010).
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21078886 C.L.Baumann, I.M.Aspalter, O.Sharif, A.Pichlmair, S.Blüml, F.Grebien, M.Bruckner, P.Pasierbek, K.Aumayr, M.Planyavsky, K.L.Bennett, J.Colinge, S.Knapp, and G.Superti-Furga (2010).
CD14 is a coreceptor of Toll-like receptors 7 and 9.
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21152039 E.Y.Kim, H.Y.Shin, J.Y.Kim, D.G.Kim, Y.M.Choi, H.K.Kwon, D.K.Rhee, Y.S.Kim, and S.Choi (2010).
ATF3 plays a key role in Kdo2-lipid A-induced TLR4-dependent gene expression via NF-κB activation.
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20133493 H.Tsukamoto, K.Fukudome, S.Takao, N.Tsuneyoshi, and M.Kimoto (2010).
Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerization enables rapid signal transduction against lipopolysaccharide stimulation on membrane-associated CD14-expressing cells.
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21286336 J.B.Soares, P.Pimentel-Nunes, R.Roncon-Albuquerque, and A.Leite-Moreira (2010).
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A five-amino-acid motif in the undefined region of the TLR8 ectodomain is required for species-specific ligand recognition.
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20018613 J.R.Riddell, X.Y.Wang, H.Minderman, and S.O.Gollnick (2010).
Peroxiredoxin 1 stimulates secretion of proinflammatory cytokines by binding to TLR4.
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20388144 J.Stagsted, A.L.Jørgensen, and H.R.Juul-Madsen (2010).
Mass spectrometric-based protein chips for detection of food-derived bioactive components.
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Advances in the design and delivery of peptide subunit vaccines with a focus on toll-like receptor agonists.
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21197425 M.Yamamoto, and K.Takeda (2010).
Current views of toll-like receptor signaling pathways.
  Gastroenterol Res Pract, 2010, 240365.  
20176798 N.Marr, A.M.Hajjar, N.R.Shah, A.Novikov, C.S.Yam, M.Caroff, and R.C.Fernandez (2010).
Substitution of the Bordetella pertussis lipid A phosphate groups with glucosamine is required for robust NF-kappaB activation and release of proinflammatory cytokines in cells expressing human but not murine Toll-like receptor 4-MD-2-CD14.
  Infect Immun, 78, 2060-2069.  
20825685 N.Matsushima, H.Miyashita, T.Mikami, and Y.Kuroki (2010).
A nested leucine rich repeat (LRR) domain: the precursor of LRRs is a ten or eleven residue motif.
  BMC Microbiol, 10, 235.  
21097929 P.C.Ronald, and B.Beutler (2010).
Plant and animal sensors of conserved microbial signatures.
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20212095 P.Prohinar, P.Rallabhandi, J.P.Weiss, and T.L.Gioannini (2010).
Expression of functional D299G.T399I polymorphic variant of TLR4 depends more on coexpression of MD-2 than does wild-type TLR4.
  J Immunol, 184, 4362-4367.  
20482318 R.A.Mariuzza, C.A.Velikovsky, L.Deng, G.Xu, and Z.Pancer (2010).
Structural insights into the evolution of the adaptive immune system: the variable lymphocyte receptors of jawless vertebrates.
  Biol Chem, 391, 753-760.  
20680392 R.Ostuni, I.Zanoni, and F.Granucci (2010).
Deciphering the complexity of Toll-like receptor signaling.
  Cell Mol Life Sci, 67, 4109-4134.  
20534476 S.I.Yoon, M.Hong, G.W.Han, and I.A.Wilson (2010).
Crystal structure of soluble MD-1 and its interaction with lipid IVa.
  Proc Natl Acad Sci U S A, 107, 10990-10995.
PDB codes: 3mtx 3mu3
20431259 S.Kusumoto, K.Fukase, and T.Shiba (2010).
Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: chemical synthesis and functional studies.
  Proc Jpn Acad Ser B Phys Biol Sci, 86, 322-337.  
20617171 S.M.Leal, S.Cowden, Y.C.Hsia, M.A.Ghannoum, M.Momany, and E.Pearlman (2010).
Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis.
  PLoS Pathog, 6, e1000976.  
20404851 T.Kawai, and S.Akira (2010).
The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors.
  Nat Immunol, 11, 373-384.  
20396414 X.Wittebole, D.Castanares-Zapatero, and P.F.Laterre (2010).
Toll-like receptor 4 modulation as a strategy to treat sepsis.
  Mediators Inflamm, 2010, 568396.  
20593217 Z.L.Chang (2010).
Important aspects of Toll-like receptors, ligands and their signaling pathways.
  Inflamm Res, 59, 791-808.  
18844294 A.Bhunia, H.Mohanram, and S.Bhattacharjya (2009).
Lipopolysaccharide bound structures of the active fragments of fowlicidin-1, a cathelicidin family of antimicrobial and antiendotoxic peptide from chicken, determined by transferred nuclear overhauser effect spectroscopy.
  Biopolymers, 92, 9.  
19302269 A.Chaturvedi, and S.K.Pierce (2009).
How location governs toll-like receptor signaling.
  Traffic, 10, 621-628.  
19359436 A.Mencin, J.Kluwe, and R.F.Schwabe (2009).
Toll-like receptors as targets in chronic liver diseases.
  Gut, 58, 704-720.  
18624726 A.Schaeffler, P.Gross, R.Buettner, C.Bollheimer, C.Buechler, M.Neumeier, A.Kopp, J.Schoelmerich, and W.Falk (2009).
Fatty acid-induced induction of Toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity.
  Immunology, 126, 233-245.  
19060881 A.Trompette, S.Divanovic, A.Visintin, C.Blanchard, R.S.Hegde, R.Madan, P.S.Thorne, M.Wills-Karp, T.L.Gioannini, J.P.Weiss, and C.L.Karp (2009).
Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein.
  Nature, 457, 585-588.  
19120489 B.Beutler (2009).
Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases.
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19252480 B.S.Park, D.H.Song, H.M.Kim, B.S.Choi, H.Lee, and J.O.Lee (2009).
The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.
  Nature, 458, 1191-1195.
PDB code: 3fxi
19543291 C.A.Velikovsky, L.Deng, S.Tasumi, L.M.Iyer, M.C.Kerzic, L.Aravind, Z.Pancer, and R.A.Mariuzza (2009).
Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen.
  Nat Struct Mol Biol, 16, 725-730.
PDB codes: 3g39 3g3a 3g3b
19099299 C.Kojima-Shibata, H.Shinkai, T.Morozumi, K.Jozaki, D.Toki, T.Matsumoto, H.Kadowaki, E.Suzuki, and H.Uenishi (2009).
Differences in distribution of single nucleotide polymorphisms among intracellular pattern recognition receptors in pigs.
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19786553 C.Morales, S.Wu, Y.Yang, B.Hao, and Z.Li (2009).
Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins.
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19556306 C.Nishitani, M.Takahashi, H.Mitsuzawa, T.Shimizu, S.Ariki, N.Matsushima, and Y.Kuroki (2009).
Mutational analysis of Cys(88) of Toll-like receptor 4 highlights the critical role of MD-2 in cell surface receptor expression.
  Int Immunol, 21, 925-934.  
  18974037 C.R.Raetz, Z.Guan, B.O.Ingram, D.A.Six, F.Song, X.Wang, and J.Zhao (2009).
Discovery of new biosynthetic pathways: the lipid A story.
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Biology and pathogenesis of the evolutionarily successful, obligate human bacterium Neisseria meningitidis.
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The path to a successful vaccine adjuvant--'the long and winding road'.
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19211304 D.Werling, O.C.Jann, V.Offord, E.J.Glass, and T.J.Coffey (2009).
Variation matters: TLR structure and species-specific pathogen recognition.
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Toll gates to periodontal host modulation and vaccine therapy.
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19556980 G.M.Barton, and J.C.Kagan (2009).
A cell biological view of Toll-like receptor function: regulation through compartmentalization.
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Pathogen recognition in the innate immune response.
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19118102 H.Shin, Y.Zhang, M.Jagannathan, H.Hasturk, A.Kantarci, H.Liu, T.E.Van Dyke, L.M.Ganley-Leal, and B.S.Nikolajczyk (2009).
B cells from periodontal disease patients express surface Toll-like receptor 4.
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19595807 I.Botos, L.Liu, Y.Wang, D.M.Segal, and D.R.Davies (2009).
The toll-like receptor 3:dsRNA signaling complex.
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19542004 J.A.Wright, S.S.Tötemeyer, I.Hautefort, C.Appia-Ayme, M.Alston, V.Danino, G.K.Paterson, P.Mastroeni, N.Ménager, M.Rolfe, A.Thompson, S.Ugrinovic, L.Sait, T.Humphrey, H.Northen, S.E.Peters, D.J.Maskell, J.C.Hinton, and C.E.Bryant (2009).
Multiple redundant stress resistance mechanisms are induced in Salmonella enterica serovar Typhimurium in response to alteration of the intracellular environment via TLR4 signalling.
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Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer.
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PDB codes: 3a79 3a7b 3a7c
19352178 K.D.Smith (2009).
Toll-like receptors in kidney disease.
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Quantitative analysis and prediction of curvature in leucine-rich repeat proteins.
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Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease.
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19847289 M.J.Jimenez-Dalmaroni, N.Xiao, A.L.Corper, P.Verdino, G.D.Ainge, D.S.Larsen, G.F.Painter, P.M.Rudd, R.A.Dwek, K.Hoebe, B.Beutler, and I.A.Wilson (2009).
Soluble CD36 ectodomain binds negatively charged diacylglycerol ligands and acts as a co-receptor for TLR2.
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Purification and characterization of the lipid A 1-phosphatase LpxE of Rhizobium leguminosarum.
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Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation.
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Essential Roles of Hydrophobic Residues in Both MD-2 and Toll-like Receptor 4 in Activation by Endotoxin.
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A peptide antagonist of the TLR4-MD2 interaction.
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The heterogeneous allelic repertoire of human toll-like receptor (TLR) genes.
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Adjuvants for malaria vaccines.
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Lipopolysaccharide binding of the mite allergen Der f 2.
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17977838 A.Teghanemt, F.Re, P.Prohinar, R.Widstrom, T.L.Gioannini, and J.P.Weiss (2008).
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18818359 B.W.Han, B.R.Herrin, M.D.Cooper, and I.A.Wilson (2008).
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PDB code: 3e6j
18559343 C.Erridge, S.Kennedy, C.M.Spickett, and D.J.Webb (2008).
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LRRCE: a leucine-rich repeat cysteine capping motif unique to the chordate lineage.
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TLR accessory molecules.
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Paclitaxel Binding to Human and Murine MD-2.
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18203953 V.Jain, A.Halle, K.A.Halmen, E.Lien, M.Charrel-Dennis, S.Ram, D.T.Golenbock, and A.Visintin (2008).
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Pathogen recognition by innate receptors.
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Design, synthesis, and evaluation of biotinylated opioid derivatives as novel probes to study opioid pharmacology.
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Two modes of ligand recognition by TLRs.
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Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide.
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PDB codes: 2z7x 2z80 2z81 2z82
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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