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Lymphokine PDB id
1tnf
Jmol
Contents
Protein chains
152 a.a. *
* Residue conservation analysis
PDB id:
1tnf
Name: Lymphokine
Title: The structure of tumor necrosis factor-alpha at 2.6 angstroms resolution. Implications for receptor binding
Structure: Tumor necrosis factor-alpha. Chain: a, b, c. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Biol. unit: Trimer (from PQS)
Resolution:
2.60Å     R-factor:   0.230    
Authors: M.J.Eck,S.R.Sprang
Key ref: M.J.Eck and S.R.Sprang (1989). The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding. J Biol Chem, 264, 17595-17605. PubMed id: 2551905
Date:
25-Aug-89     Release date:   15-Jan-90    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P01375  (TNFA_HUMAN) -  Tumor necrosis factor
Seq:
Struc: 		233 a.a.
152 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     immune response   1 term 
  Biochemical function     tumor necrosis factor receptor binding     1 term  

 

 
J Biol Chem 264:17595-17605 (1989)
PubMed id: 2551905  
 
 
The structure of tumor necrosis factor-alpha at 2.6 A resolution. Implications for receptor binding.
M.J.Eck, S.R.Sprang.
 
  ABSTRACT  
 
The three-dimensional structure of tumor necrosis factor (TNF-alpha), a protein hormone secreted by macrophages, has been determined at 2.6 A resolution by x-ray crystallography. Phases were determined by multiple isomorphous replacement using data collected from five heavy atom derivatives. The multiple isomorphous replacement phases were further improved by real space symmetry averaging, exploiting the noncrystallographic 3-fold symmetry of the TNF-alpha trimer. An atomic model corresponding to the known amino acid sequence of TNF-alpha was readily built into the electron density map calculated with these improved phases. The 17,350-dalton monomer forms an elongated, antiparallel beta-pleated sheet sandwich with a "jelly-roll" topology. Three monomers associate intimately about a 3-fold axis of symmetry to form a compact bell-shaped trimer. Examination of the model and comparison to known protein structures reveals striking structural homology to several viral coat proteins, particularly satellite tobacco necrosis virus. Locations of residues conserved between TNF-alpha and lymphotoxin (TNF-beta, a related cytokine known to bind to the same receptors as TNF-alpha) suggest that lymphotoxin, like TNF-alpha, binds to the receptor as a trimer and that the general site of interaction with the receptor is at the "base" of the trimer.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20571888 P.Kleinbongard, R.Schulz, and G.Heusch (2011).
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Ligand-receptor binding revealed by the TNF family member TALL-1.
  Nature, 423, 49-56.
PDB codes: 1oqd 1oqe
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Association of human tumor necrosis factor-related apoptosis inducing ligand with membrane upon acidification.
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Autoantibodies to TNFalpha in HIV-1 infection: prospects for anti-cytokine vaccine therapy.
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11239407 R.M.Locksley, N.Killeen, and M.J.Lenardo (2001).
The TNF and TNF receptor superfamilies: integrating mammalian biology.
  Cell, 104, 487-501.  
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Construction and analysis of three-dimensional graphic model of single-chain Fv derived from an anti-human placental acidic isoferritin monoclonal antibody by computer.
  J Tongji Med Univ, 20, 23-25.  
11114500 E.Y.Jones (2000).
The tumour necrosis factor receptor family: life or death choices.
  Curr Opin Struct Biol, 10, 644-648.  
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TNF alpha and the TNF receptor superfamily: structure-function relationship(s).
  Microsc Res Tech, 50, 184-195.  
10908665 H.Ye, and H.Wu (2000).
Thermodynamic characterization of the interaction between TRAF2 and tumor necrosis factor receptor peptides by isothermal titration calorimetry.
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PDB code: 1dg6
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11057900 S.W.Fesik (2000).
Insights into programmed cell death through structural biology.
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Protein structural topology: Automated analysis and diagrammatic representation.
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Inhibition of tumor necrosis factor-alpha (TNF-alpha)/TNF-alpha receptor binding by structural analogues of suramin.
  Biochem Pharmacol, 58, 851-859.  
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The structure of mouse tumour-necrosis factor at 1.4 A resolution: towards modulation of its selectivity and trimerization.
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PDB code: 2tnf
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Thiolated recombinant human tumor necrosis factor-alpha protects against Plasmodium berghei K173-induced experimental cerebral malaria in mice.
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TWEAK can induce cell death via endogenous TNF and TNF receptor 1.
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PDB code: 1d0g
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Expression, purification and crystallization of recombinant human TRAIL.
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2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity.
  Immunity, 11, 253-261.
PDB code: 1d2q
10433725 S.S.Pullen, M.E.Labadia, R.H.Ingraham, S.M.McWhirter, D.S.Everdeen, T.Alber, J.J.Crute, and M.R.Kehry (1999).
High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization.
  Biochemistry, 38, 10168-10177.  
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LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator.
  Immunity, 8, 21-30.  
  9765392 G.Lu, Z.H.Zhou, M.L.Baker, J.Jakana, D.Cai, X.Wei, S.Chen, X.Gu, and W.Chiu (1998).
Structure of double-shelled rice dwarf virus.
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The role of polar interactions in the molecular recognition of CD40L with its receptor CD40.
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9512423 L.Shapiro, and P.E.Scherer (1998).
The crystal structure of a complement-1q family protein suggests an evolutionary link to tumor necrosis factor.
  Curr Biol, 8, 335-338.
PDB code: 1c28
9669810 T.A.Tran, B.V.Kallakury, R.A.Ambros, and J.S.Ross (1998).
Prognostic significance of tumor necrosis factors and their receptors in nonsmall cell lung carcinoma.
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Getting it together: signal transduction in G-protein coupled receptors by association of receptor domains.
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Molecular, structural, and biological characteristics of the tumor necrosis factor ligand superfamily.
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The crystal structure of human glycosylation-inhibiting factor is a trimeric barrel with three 6-stranded beta-sheets.
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PDB code: 1gif
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2 A crystal structure of an extracellular fragment of human CD40 ligand.
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PDB code: 1aly
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Functional discrepancies between tumor necrosis factor and lymphotoxin alpha explained by trimer stability and distinct receptor interactions.
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The folding and assembly pathway of tumour necrosis factor TNF alpha, a globular trimeric protein.
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An evolutionary and functional approach to the TNF receptor/ligand family.
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A family of ligands for the TNF receptor superfamily.
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Structural and functional basis for hormone binding and receptor oligomerization.
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The TNF Receptors p55 and p75 Mediate Chemotaxis of PMN Induced by TNFalpha and a TNFalpha 36-62 Peptide.
  Mediators Inflamm, 3, 347-352.  
  8076595 P.R.Baum, R.B.Gayle, F.Ramsdell, S.Srinivasan, R.A.Sorensen, M.L.Watson, M.F.Seldin, E.Baker, G.R.Sutherland, and K.N.Clifford (1994).
Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34.
  EMBO J, 13, 3992-4001.  
7964492 T.J.Evans, D.Moyes, A.Carpenter, R.Martin, H.Loetscher, W.Lesslauer, and J.Cohen (1994).
Protective effect of 55- but not 75-kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in an animal model of gram-negative sepsis.
  J Exp Med, 180, 2173-2179.  
7511063 T.Takahashi, M.Tanaka, C.I.Brannan, N.A.Jenkins, N.G.Copeland, T.Suda, and S.Nagata (1994).
Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.
  Cell, 76, 969-976.  
7678782 A.Aruffo, M.Farrington, D.Hollenbaugh, X.Li, A.Milatovich, S.Nonoyama, J.Bajorath, L.S.Grosmaire, R.Stenkamp, and M.Neubauer (1993).
The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome.
  Cell, 72, 291-300.  
9137562 B.L.Kagan, T.Mirzabekov, D.Munoz, R.L.Baldwin, and B.Wisnieski (1993).
The role of channel formation in the mechanism of action of tumor necrosis factors.
  Ann N Y Acad Sci, 707, 317-327.  
8391931 C.A.Smith, H.J.Gruss, T.Davis, D.Anderson, T.Farrah, E.Baker, G.R.Sutherland, C.I.Brannan, N.G.Copeland, and N.A.Jenkins (1993).
CD30 antigen, a marker for Hodgkin's lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF.
  Cell, 73, 1349-1360.  
8387891 D.W.Banner, A.D'Arcy, W.Janes, R.Gentz, H.J.Schoenfeld, C.Broger, H.Loetscher, and W.Lesslauer (1993).
Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation.
  Cell, 73, 431-445.
PDB code: 1tnr
  7505680 J.Bajorath, R.Stenkamp, and A.Aruffo (1993).
Knowledge-based model building of proteins: concepts and examples.
  Protein Sci, 2, 1798-1810.
PDB code: 1kjd
8405064 R.G.Goodwin, W.S.Din, T.Davis-Smith, D.M.Anderson, S.D.Gimpel, T.A.Sato, C.R.Maliszewski, C.I.Brannan, N.G.Copeland, and N.A.Jenkins (1993).
Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor.
  Eur J Immunol, 23, 2631-2641.  
  8390056 R.S.Sidhu, and A.P.Bollon (1993).
Tumor necrosis factor activities and cancer therapy--a perspective.
  Pharmacol Ther, 57, 79.  
7505205 T.Suda, T.Takahashi, P.Golstein, and S.Nagata (1993).
Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family.
  Cell, 75, 1169-1178.  
  8415875 Y.Mitsui, T.Senda, T.Shimazu, S.Matsuda, and J.Utsumi (1993).
Structural, functional and evolutionary implications of the three-dimensional crystal structure of murine interferon-beta.
  Pharmacol Ther, 58, 93.  
  1607009 A.Brass, K.E.Kadler, J.T.Thomas, M.E.Grant, and R.P.Boot-Handford (1992).
The fibrillar collagens, collagen VIII, collagen X and the C1q complement proteins share a similar domain in their C-terminal non-collagenous regions.
  FEBS Lett, 303, 126-128.  
1310100 D.Aderka, H.Engelmann, Y.Maor, C.Brakebusch, and D.Wallach (1992).
Stabilization of the bioactivity of tumor necrosis factor by its soluble receptors.
  J Exp Med, 175, 323-329.  
  1385114 D.Hollenbaugh, L.S.Grosmaire, C.D.Kullas, N.J.Chalupny, S.Braesch-Andersen, R.J.Noelle, I.Stamenkovic, J.A.Ledbetter, and A.Aruffo (1992).
The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.
  EMBO J, 11, 4313-4321.  
1331273 J.Rothe, G.Gehr, H.Loetscher, and W.Lesslauer (1992).
Tumor necrosis factor receptors--structure and function.
  Immunol Res, 11, 81-90.  
1528078 M.D.Walkinshaw (1992).
Protein targets for structure-based drug design.
  Med Res Rev, 12, 317-372.  
  1373060 R.H.Stiemer, U.Westenfelder, H.Gausepohl, M.Mirshahi, A.Gundt, R.W.Frank, and D.N.Männel (1992).
A common epitope on human tumor necrosis factor alpha and the autoantigen 'S-antigen/arrestin' induces TNF-alpha production.
  J Autoimmun, 5, 15-26.  
  1505514 T.Senda, T.Shimazu, S.Matsuda, G.Kawano, H.Shimizu, K.T.Nakamura, and Y.Mitsui (1992).
Three-dimensional crystal structure of recombinant murine interferon-beta.
  EMBO J, 11, 3193-3201.
PDB code: 1ifa
1660140 A.Ashkenazi, S.A.Marsters, D.J.Capon, S.M.Chamow, I.S.Figari, D.Pennica, D.V.Goeddel, M.A.Palladino, and D.H.Smith (1991).
Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin.
  Proc Natl Acad Sci U S A, 88, 10535-10539.  
1786996 A.D.Nash, G.J.Barcham, M.R.Brandon, and A.E.Andrews (1991).
Molecular cloning, expression and characterization of ovine TNF alpha.
  Immunol Cell Biol, 69, 273-283.  
1647190 B.B.Aggarwal (1991).
Structure of tumor necrosis factor and its receptor.
  Biotherapy, 3, 113-120.  
1657606 G.Camussi, E.Albano, C.Tetta, and F.Bussolino (1991).
The molecular action of tumor necrosis factor-alpha.
  Eur J Biochem, 202, 3.  
1849658 J.D.Zhang, L.S.Cousens, P.J.Barr, and S.R.Sprang (1991).
Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta.
  Proc Natl Acad Sci U S A, 88, 3446-3450.
PDB code: 2fgf
1742163 J.H.Riazance-Lawrence, A.Toumadje, and W.C.Johnson (1991).
The circular dichroism of tumor necrosis factor-alpha: measurement into the vacuum UV and analysis for secondary structure.
  Chirality, 3, 254-256.  
  1916847 S.D.Gillies, D.Young, K.M.Lo, S.F.Foley, and R.A.Reisfeld (1991).
Expression of genetically engineered immunoconjugates of lymphotoxin and a chimeric anti-ganglioside GD2 antibody.
  Hybridoma, 10, 347-356.  
  1649771 W.Fiers (1991).
Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level.
  FEBS Lett, 285, 199-212.  
  2009860 X.Van Ostade, J.Tavernier, T.Prangé, and W.Fiers (1991).
Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis.
  EMBO J, 10, 827-836.  
2258704 A.E.Postlethwaite, and J.M.Seyer (1990).
Stimulation of fibroblast chemotaxis by human recombinant tumor necrosis factor alpha (TNF-alpha) and a synthetic TNF-alpha 31-68 peptide.
  J Exp Med, 172, 1749-1756.  
1702293 A.Himmler, I.Maurer-Fogy, M.Krönke, P.Scheurich, K.Pfizenmaier, M.Lantz, I.Olsson, R.Hauptmann, C.Stratowa, and G.R.Adolf (1990).
Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p60) and its soluble derivative, tumor necrosis factor-binding protein.
  DNA Cell Biol, 9, 705-715.  
2164226 P.Seckinger, J.H.Zhang, B.Hauptmann, and J.M.Dayer (1990).
Characterization of a tumor necrosis factor alpha (TNF-alpha) inhibitor: evidence of immunological cross-reactivity with the TNF receptor.
  Proc Natl Acad Sci U S A, 87, 5188-5192.  
2174582 S.R.Sprang (1990).
The divergent receptors for TNF.
  Trends Biochem Sci, 15, 366-368.  
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 codes are shown on the right.