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3alq

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3alq, resolution 3.00Å ()
Ligands:
Gene: TNF, TNFA, TNFSF2 (Homo sapiens), TNFBR, TNFR2, TNFRSF1B (Homo sapiens)
Related: 1tnr, 1tnf, 2e7a, 2zjc, 2zpx


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of TNF-TNFR2 complex

Publication Abstract from PubMed

Tumor necrosis factor (TNF) is an inflammatory cytokine that has important roles in various immune responses, which are mediated through its two receptors, TNF receptor 1 (TNFR1) and TNFR2. Antibody-based therapy against TNF is used clinically to treat several chronic autoimmune diseases; however, such treatment sometimes results in serious side effects, which are thought to be caused by the blocking of signals from both TNFRs. Therefore, knowledge of the structural basis for the recognition of TNF by each receptor would be invaluable in designing TNFR-selective drugs. Here, we solved the 3.0 angstrom resolution structure of the TNF-TNFR2 complex, which provided insight into the molecular recognition of TNF by TNFR2. Comparison to the known TNFR1 structure highlighted several differences between the ligand-binding interfaces of the two receptors. Additionally, we also demonstrated that TNF-TNFR2 formed aggregates on the surface of cells, which may be required for signal initiation. These results may contribute to the design of therapeutics for autoimmune diseases.

Solution of the Structure of the TNF-TNFR2 Complex., Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S, Nakagawa S, Yamagata Y, Tsutsumi Y, Sci Signal. 2010 Nov 16;3(148):ra83. PMID:21081755

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[TNFA_HUMAN] Genetic variations in TNF are a cause of susceptibility psoriatic arthritis (PSORAS) [MIM:607507]. PSORAS is an inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoidlike pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).

Function

[TNFA_HUMAN] Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.[1] The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.[2] [TNR1B_HUMAN] Receptor with high affinity for TNFSF2/TNF-alpha and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF-alpha. Isoform 2 blocks TNF-alpha-induced apoptosis, which suggests that it regulates TNF-alpha function by antagonizing its biological activity.[3][4]

About this Structure

3alq is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

  • Mukai Y, Nakamura T, Yoshikawa M, Yoshioka Y, Tsunoda S, Nakagawa S, Yamagata Y, Tsutsumi Y. Solution of the Structure of the TNF-TNFR2 Complex. Sci Signal. 2010 Nov 16;3(148):ra83. PMID:21081755 doi:10.1126/scisignal.2000954
  1. Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
  2. Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production. Nat Cell Biol. 2006 Aug;8(8):843-8. Epub 2006 Jul 9. PMID:16829952 doi:10.1038/ncb1440
  3. Lainez B, Fernandez-Real JM, Romero X, Esplugues E, Canete JD, Ricart W, Engel P. Identification and characterization of a novel spliced variant that encodes human soluble tumor necrosis factor receptor 2. Int Immunol. 2004 Jan;16(1):169-77. PMID:14688072
  4. Pan S, An P, Zhang R, He X, Yin G, Min W. Etk/Bmx as a tumor necrosis factor receptor type 2-specific kinase: role in endothelial cell migration and angiogenesis. Mol Cell Biol. 2002 Nov;22(21):7512-23. PMID:12370298

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