PDBsum entry 1fyx

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Signaling protein PDB id
Protein chain
149 a.a. *
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Crystal structure of p681h mutant of tir domain of human tlr
Structure: Toll-like receptor 2. Chain: a. Fragment: tir domain. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Biol. unit: Dimer (from PQS)
2.80Å     R-factor:   0.242     R-free:   0.284
Authors: Y.Xu,X.Tao,B.Shen,T.Horng,R.Medzhitov,J.L.Manley,L.Tong
Key ref:
Y.Xu et al. (2000). Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature, 408, 111-115. PubMed id: 11081518 DOI: 10.1038/35040600
03-Oct-00     Release date:   22-Nov-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O60603  (TLR2_HUMAN) -  Toll-like receptor 2
784 a.a.
149 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     integral to membrane   1 term 
  Biological process     signal transduction   8 terms 


DOI no: 10.1038/35040600 Nature 408:111-115 (2000)
PubMed id: 11081518  
Structural basis for signal transduction by the Toll/interleukin-1 receptor domains.
Y.Xu, X.Tao, B.Shen, T.Horng, R.Medzhitov, J.L.Manley, L.Tong.
Toll-like receptors (TLRs) and the interleukin-1 receptor superfamily (IL-1Rs) are integral to both innate and adaptive immunity for host defence. These receptors share a conserved cytoplasmic domain, known as the TIR domain. A single-point mutation in the TIR domain of murine TLR4 (Pro712His, the Lps(d) mutation) abolishes the host immune response to lipopolysaccharide (LPS), and mutation of the equivalent residue in TLR2, Pro681His, disrupts signal transduction in response to stimulation by yeast and gram-positive bacteria. Here we report the crystal structures of the TIR domains of human TLR1 and TLR2 and of the Pro681His mutant of TLR2. The structures have a large conserved surface patch that also contains the site of the Lps(d) mutation. Mutagenesis and functional studies confirm that residues in this surface patch are crucial for receptor signalling. The Lps(d) mutation does not disturb the structure of the TIR domain itself. Instead, structural and functional studies indicate that the conserved surface patch may mediate interactions with the down-stream MyD88 adapter molecule, and that the Lps(d) mutation may abolish receptor signalling by disrupting this recruitment.
  Selected figure(s)  
Figure 1.
Figure 1: Structures of the TIR domain. a, Drawing of the structure of the TIR domain of human TLR2. Three missing residues, 723-725, are shown in grey. b, Superposition of the C traces of the structures of the TIR domain of human TLR1 (cyan) and TLR2 (yellow). Regions of large differences between the two structures are labelled. c, Superposition of the C traces of the structures of the TIR domain of human TLR2 wild type (yellow) and the P681H mutant (grey). The side chains of residue 681 are shown. d, Alignment of representative TIR domain sequences. The secondary structure elements (SS) are labelled. Amino-acid sequence conservation (Cons.) is indicated by the consensus residue name or a purple bar. Cyan bars indicate residues conserved in IL-1Rs or TLRs only. Residues in the hydrophobic core of the two structures (with less than 25% exposed surface area) are coloured in green. a produced with Ribbons 28, b and c with Grasp29.
Figure 2.
Figure 2: Structural analysis of the TIR domains. a, A large patch of conserved surface involving residues in the BB loop. Molecular surface of the TIR domain of TLR2 is shown. Conserved residues are highlighted in -strands (cyan) in helices (yellow), in the BB loop (purple) and in other loops (green). The site of the Lpsd mutation (Pro BB7) is coloured in red. b, Drawing of the residues contributing to the conserved surface patch shown in a, in a similar orientation and colouring scheme. Also shown is the ion-pair between Arg BB3 and Glu A13. a produced with Grasp29 and b with Ribbons 28.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2000, 408, 111-115) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21198355 J.J.Khoo, S.Forster, and A.Mansell (2011).
Toll-like receptors as interferon-regulated genes and their role in disease.
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20354830 H.Ohnishi, H.Tochio, Z.Kato, T.Kimura, H.Hiroaki, N.Kondo, and M.Shirakawa (2010).
1H, 13C, and 15N resonance assignment of the TIR domain of human MyD88.
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20396665 K.Nasu, and H.Narahara (2010).
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The crystal structure of a TIR domain from Arabidopsis thaliana reveals a conserved helical region unique to plants.
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PDB code: 3jrn
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19229585 A.O.Tarakanov, K.G.Fuxe, L.F.Agnati, and L.B.Goncharova (2009).
Possible role of receptor heteromers in multiple sclerosis.
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Expression and immune effect of toll-like receptor 4 in human trophoblast cells.
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19308258 G.A.Gomez, M.B.Veldman, Y.Zhao, S.Burgess, and S.Lin (2009).
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19196716 G.K.Radhakrishnan, Q.Yu, J.S.Harms, and G.A.Splitter (2009).
Brucella TIR Domain-containing Protein Mimics Properties of the Toll-like Receptor Adaptor Protein TIRAP.
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19376887 G.Zanotti, M.Casiraghi, J.B.Abano, J.R.Tatreau, M.Sevala, H.Berlin, S.Smyth, W.K.Funkhouser, K.Burridge, S.H.Randell, and T.M.Egan (2009).
Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema.
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19506249 H.Ohnishi, H.Tochio, Z.Kato, K.E.Orii, A.Li, T.Kimura, H.Hiroaki, N.Kondo, and M.Shirakawa (2009).
Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling.
  Proc Natl Acad Sci U S A, 106, 10260-10265.
PDB code: 2z5v
19509286 K.Nagpal, T.S.Plantinga, J.Wong, B.G.Monks, N.J.Gay, M.G.Netea, K.A.Fitzgerald, and D.T.Golenbock (2009).
A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling.
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19289601 M.H.Laird, S.H.Rhee, D.J.Perkins, A.E.Medvedev, W.Piao, M.J.Fenton, and S.N.Vogel (2009).
TLR4/MyD88/PI3K interactions regulate TLR4 signaling.
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19470169 M.R.Bhide, R.Mucha, I.Mikula, L.Kisova, R.Skrabana, M.Novak, and I.Mikula (2009).
Novel mutations in TLR genes cause hyporesponsiveness to Mycobacterium avium subsp. paratuberculosis infection.
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19627256 S.Carpenter, and L.A.O'Neill (2009).
Recent insights into the structure of Toll-like receptors and post-translational modifications of their associated signalling proteins.
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19535337 S.L.Chan, L.Y.Low, S.Hsu, S.Li, T.Liu, E.Santelli, G.Le Negrate, J.C.Reed, V.L.Woods, and J.Pascual (2009).
Molecular Mimicry in Innate Immunity: CRYSTAL STRUCTURE OF A BACTERIAL TIR DOMAIN.
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PDB code: 3h16
19648648 S.W.Wong, M.J.Kwon, A.M.Choi, H.P.Kim, K.Nakahira, and D.H.Hwang (2009).
Fatty acids modulate Toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner.
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19064998 S.Yanagimoto, K.Tatsuno, S.Okugawa, T.Kitazawa, K.Tsukada, K.Koike, T.Kodama, S.Kimura, Y.Shibasaki, and Y.Ota (2009).
A Single Amino Acid of Toll-like Receptor 4 That Is Pivotal for Its Signal Transduction and Subcellular Localization.
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18810334 T.Xiao (2009).
Innate immune recognition of nucleic acids.
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18227810 F.Leulier, and B.Lemaitre (2008).
Toll-like receptors--taking an evolutionary approach.
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18178098 F.Shen, and S.L.Gaffen (2008).
Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy.
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18369614 J.Su, Z.Zhu, Y.Wang, J.Zou, and W.Hu (2008).
Toll-like receptor 3 regulates Mx expression in rare minnow Gobiocypris rarus after viral infection.
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18450748 K.Funami, M.Sasai, H.Oshiumi, T.Seya, and M.Matsumoto (2008).
Homo-oligomerization is essential for Toll/interleukin-1 receptor domain-containing adaptor molecule-1-mediated NF-kappaB and interferon regulatory factor-3 activation.
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MutL homologs in restriction-modification systems and the origin of eukaryotic MORC ATPases.
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18395849 M.A.Eskan, B.G.Rose, M.R.Benakanakere, Q.Zeng, D.Fujioka, M.H.Martin, M.J.Lee, and D.F.Kinane (2008).
TLR4 and S1P receptors cooperate to enhance inflammatory cytokine production in human gingival epithelial cells.
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18332211 M.A.Eskan, M.R.Benakanakere, B.G.Rose, P.Zhang, J.Zhao, P.Stathopoulou, D.Fujioka, and D.F.Kinane (2008).
Interleukin-1beta modulates proinflammatory cytokine production in human epithelial cells.
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18937834 O.C.Jann, D.Werling, J.S.Chang, D.Haig, and E.J.Glass (2008).
Molecular evolution of bovine Toll-like receptor 2 suggests substitutions of functional relevance.
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18827826 R.Kakkar, and R.T.Lee (2008).
The IL-33/ST2 pathway: therapeutic target and novel biomarker.
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18332149 T.Nyman, P.Stenmark, S.Flodin, I.Johansson, M.Hammarström, and P.Nordlund (2008).
The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer.
  J Biol Chem, 283, 11861-11865.
PDB code: 2j67
17456598 A.Maitra, F.Shen, W.Hanel, K.Mossman, J.Tocker, D.Swart, and S.L.Gaffen (2007).
Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression.
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17727694 E.K.Kruithof, N.Satta, J.W.Liu, S.Dunoyer-Geindre, and R.J.Fish (2007).
Gene conversion limits divergence of mammalian TLR1 and TLR6.
  BMC Evol Biol, 7, 148.  
17673666 G.Chen, O.Zhuchenko, and A.Kuspa (2007).
Immune-like phagocyte activity in the social amoeba.
  Science, 317, 678-681.  
17375196 I.Glezer, A.Chernomoretz, S.David, M.M.Plante, and S.Rivest (2007).
Genes involved in the balance between neuronal survival and death during inflammation.
  PLoS ONE, 2, e310.  
17457343 L.A.O'Neill, and A.G.Bowie (2007).
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling.
  Nat Rev Immunol, 7, 353-364.  
17290189 M.R.Chicoine, M.Zahner, E.K.Won, R.R.Kalra, T.Kitamura, A.Perry, and R.Higashikubo (2007).
The in vivo antitumoral effects of lipopolysaccharide against glioblastoma multiforme are mediated in part by Toll-like receptor 4.
  Neurosurgery, 60, 372.  
17726518 R.Núñez Miguel, J.Wong, J.F.Westoll, H.J.Brooks, L.A.O'Neill, N.J.Gay, C.E.Bryant, and T.P.Monie (2007).
A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.
  PLoS ONE, 2, e788.  
17607319 T.Huyton, J.Rossjohn, and M.Wilce (2007).
Toll-like receptors: structural pieces of a curve-shaped puzzle.
  Immunol Cell Biol, 85, 406-410.  
17227763 T.Into, Y.Kanno, J.Dohkan, M.Nakashima, M.Inomata, K.Shibata, C.J.Lowenstein, and K.Matsushita (2007).
Pathogen recognition by Toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells.
  J Biol Chem, 282, 8134-8141.  
17667936 T.M.Watters, E.F.Kenny, and L.A.O'Neill (2007).
Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins.
  Immunol Cell Biol, 85, 411-419.  
17331607 W.Low, A.Mortlock, L.Petrovska, T.Dottorini, G.Dougan, and A.Crisanti (2007).
Functional cell permeable motifs within medically relevant proteins.
  J Biotechnol, 129, 555-564.  
17496895 Y.J.Kang, S.O.Kim, S.Shimada, M.Otsuka, A.Seit-Nebi, B.S.Kwon, T.H.Watts, and J.Han (2007).
Cell surface 4-1BBL mediates sequential signaling pathways 'downstream' of TLR and is required for sustained TNF production in macrophages.
  Nat Immunol, 8, 601-609.  
17724133 Y.Kim, P.Zhou, L.Qian, J.Z.Chuang, J.Lee, C.Li, C.Iadecola, C.Nathan, and A.Ding (2007).
MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival.
  J Exp Med, 204, 2063-2074.  
17110940 B.J.DeYoung, and R.W.Innes (2006).
Plant NBS-LRR proteins in pathogen sensing and host defense.
  Nat Immunol, 7, 1243-1249.  
16990271 C.A.Leifer, J.C.Brooks, K.Hoelzer, J.Lopez, M.N.Kennedy, A.Mazzoni, and D.M.Segal (2006).
Cytoplasmic targeting motifs control localization of toll-like receptor 9.
  J Biol Chem, 281, 35585-35592.  
16968706 C.Fearns, Q.Pan, J.C.Mathison, and T.H.Chuang (2006).
Triad3A regulates ubiquitination and proteasomal degradation of RIP1 following disruption of Hsp90 binding.
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16720699 J.K.Bell, J.Askins, P.R.Hall, D.R.Davies, and D.M.Segal (2006).
The dsRNA binding site of human Toll-like receptor 3.
  Proc Natl Acad Sci U S A, 103, 8792-8797.  
16893894 J.K.Gautam, Ashish, L.D.Comeau, J.K.Krueger, and M.F.Smith (2006).
Structural and functional evidence for the role of the TLR2 DD loop in TLR1/TLR2 heterodimerization and signaling.
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16677430 L.McHale, X.Tan, P.Koehl, and R.W.Michelmore (2006).
Plant NBS-LRR proteins: adaptable guards.
  Genome Biol, 7, 212.  
17330145 M.K.Purcell, K.D.Smith, L.Hood, J.R.Winton, and J.C.Roach (2006).
Conservation of Toll-Like Receptor Signaling Pathways in Teleost Fish.
  Comp Biochem Physiol Part D Genomics Proteomics, 1, 77-88.  
16917510 N.J.Gay, M.Gangloff, and A.N.Weber (2006).
Toll-like receptors as molecular switches.
  Nat Rev Immunol, 6, 693-698.  
16714536 P.Henneke, and R.Berner (2006).
Interaction of neonatal phagocytes with group B streptococcus: recognition and response.
  Infect Immun, 74, 3085-3095.  
16369016 R.M.Newman, P.Salunkhe, A.Godzik, and J.C.Reed (2006).
Identification and characterization of a novel bacterial virulence factor that shares homology with mammalian Toll/interleukin-1 receptor family proteins.
  Infect Immun, 74, 594-601.  
16849232 S.Fletcher, and A.D.Hamilton (2006).
Targeting protein-protein interactions by rational design: mimicry of protein surfaces.
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16645488 S.Kenzel, and P.Henneke (2006).
The innate immune system and its relevance to neonatal sepsis.
  Curr Opin Infect Dis, 19, 264-270.  
16482509 V.Brown, R.A.Brown, A.Ozinsky, J.R.Hesselberth, and S.Fields (2006).
Binding specificity of Toll-like receptor cytoplasmic domains.
  Eur J Immunol, 36, 742-753.  
16832055 Z.Jiang, P.Georgel, C.Li, J.Choe, K.Crozat, S.Rutschmann, X.Du, T.Bigby, S.Mudd, S.Sovath, I.A.Wilson, A.Olson, and B.Beutler (2006).
Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis.
  Proc Natl Acad Sci U S A, 103, 10961-10966.  
16131923 A.Micera, B.Stampachiacchiere, S.Aronni, M.S.dos Santos, and A.Lambiase (2005).
Toll-like receptors and the eye.
  Curr Opin Allergy Clin Immunol, 5, 451-458.  
15849357 C.Li, J.Zienkiewicz, and J.Hawiger (2005).
Interactive sites in the MyD88 Toll/interleukin (IL) 1 receptor domain responsible for coupling to the IL1beta signaling pathway.
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15840688 E.Cario (2005).
Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2.
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15954154 H.Yin, and A.D.Hamilton (2005).
Strategies for targeting protein-protein interactions with synthetic agents.
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16043704 J.K.Bell, I.Botos, P.R.Hall, J.Askins, J.Shiloach, D.M.Segal, and D.R.Davies (2005).
The molecular structure of the Toll-like receptor 3 ligand-binding domain.
  Proc Natl Acad Sci U S A, 102, 10976-10980.
PDB code: 2a0z
15767367 J.Stack, I.R.Haga, M.Schröder, N.W.Bartlett, G.Maloney, P.C.Reading, K.A.Fitzgerald, G.L.Smith, and A.G.Bowie (2005).
Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence.
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15755740 M.Loiarro, C.Sette, G.Gallo, A.Ciacci, N.Fantò, D.Mastroianni, P.Carminati, and V.Ruggiero (2005).
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15384042 A.F.Cunningham, M.Khan, J.Ball, K.M.Toellner, K.Serre, E.Mohr, and I.C.MacLennan (2004).
Responses to the soluble flagellar protein FliC are Th2, while those to FliC on Salmonella are Th1.
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15452057 A.Kumar, J.Zhang, and F.S.Yu (2004).
Innate immune response of corneal epithelial cells to Staphylococcus aureus infection: role of peptidoglycan in stimulating proinflammatory cytokine secretion.
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14699116 H.K.Lee, S.Dunzendorfer, and P.S.Tobias (2004).
Cytoplasmic domain-mediated dimerizations of toll-like receptor 4 observed by beta-lactamase enzyme fragment complementation.
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15548971 H.Methe, E.Zimmer, C.Grimm, M.Nabauer, and J.Koglin (2004).
Evidence for a role of toll-like receptor 4 in development of chronic allograft rejection after cardiac transplantation.
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15123616 J.A.Khan, E.K.Brint, L.A.O'Neill, and L.Tong (2004).
Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL.
  J Biol Chem, 279, 31664-31670.
PDB code: 1t3g
15123841 N.T.Liberati, K.A.Fitzgerald, D.H.Kim, R.Feinbaum, D.T.Golenbock, and F.M.Ausubel (2004).
Requirement for a conserved Toll/interleukin-1 resistance domain protein in the Caenorhabditis elegans immune response.
  Proc Natl Acad Sci U S A, 101, 6593-6598.  
15039311 P.Kropf, M.A.Freudenberg, M.Modolell, H.P.Price, S.Herath, S.Antoniazi, C.Galanos, D.F.Smith, and I.Müller (2004).
Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major.
  Infect Immun, 72, 1920-1928.  
18629061 R.G.Allaby, and M.Woodwark (2004).
Phylogenetics in the bioinformatics culture of understanding.
  Comp Funct Genomics, 5, 128-146.  
15229469 S.Akira, and K.Takeda (2004).
Toll-like receptor signalling.
  Nat Rev Immunol, 4, 499-511.  
15578265 S.K.Sanghavi, R.Shankarappa, and T.A.Reinhart (2004).
Genetic analysis of Toll/Interleukin-1 Receptor (TIR) domain sequences from rhesus macaque Toll-like receptors (TLRs) 1-10 reveals high homology to human TLR/TIR sequences.
  Immunogenetics, 56, 667-674.  
15197269 X.Hu, Y.Yagi, T.Tanji, S.Zhou, and Y.T.Ip (2004).
Multimerization and interaction of Toll and Spätzle in Drosophila.
  Proc Natl Acad Sci U S A, 101, 9369-9374.  
12888566 A.Dunne, M.Ejdeback, P.L.Ludidi, L.A.O'Neill, and N.J.Gay (2003).
Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors Mal and MyD88.
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12826024 C.A.Wells, T.Ravasi, G.J.Faulkner, P.Carninci, Y.Okazaki, Y.Hayashizaki, M.Sweet, B.J.Wainwright, and D.A.Hume (2003).
Genetic control of the innate immune response.
  BMC Immunol, 4, 5.  
14519765 H.Oshiumi, M.Sasai, K.Shida, T.Fujita, M.Matsumoto, and T.Seya (2003).
TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting to toll-like receptor 4 TICAM-1 that induces interferon-beta.
  J Biol Chem, 278, 49751-49762.  
12819136 J.C.Reed, K.Doctor, A.Rojas, J.M.Zapata, C.Stehlik, L.Fiorentino, J.Damiano, W.Roth, S.Matsuzawa, R.Newman, S.Takayama, H.Marusawa, F.Xu, G.Salvesen, and A.Godzik (2003).
Comparative analysis of apoptosis and inflammation genes of mice and humans.
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PDB code: 1p95
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14638766 S.R.Coats, R.A.Reife, B.W.Bainbridge, T.T.Pham, and R.P.Darveau (2003).
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COMO: a program for combined molecular replacement.
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