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4g3y

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4g3y, resolution 2.60Å ()
Gene: TNFA (Gekko coi)
Related: 4g3z


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


Contents

Crystal structure of TNF-alpha in complex with Infliximab Fab fragment

Publication Abstract from PubMed

BACKGROUND: Although infliximab has high efficacy in treating TNFalpha-associated diseases, the epitope on TNFalpha remains unclear. RESULTS: The crystal structure of the TNFalpha in complex with the infliximab Fab is reported at a resolution of 2.6 A. CONCLUSION: TNFalpha E-F loop plays a crucial role in the interaction. SIGNIFICANCE: The structure may lead to understanding the mechanism of mAb anti-TNFalpha Monoclonal antibody (mAb) drugs have been widely used for treating tumor necrosis factor alpha (TNFalpha)-related diseases for over 10 years. Although their action has been hypothesized to depend in part on their ability to bind precursor cell surface TNFalpha, the precise mechanism and the epitope bound on TNFalpha remain unclear. In the present work, we report the crystal structure of the infliximab Fab fragment in complex with TNFalpha at a resolution of 2.6 A. The key features of the TNFalpha E-F loop region in this complex distinguish the interaction between infliximab and TNFalpha from other TNF-receptor structures, revealing the mechanism of TNFalpha inhibition by overlapping with the TNFalpha-receptor interface and indicating the crucial role of the E-F loop in the action of this therapeutic antibody. This structure also indicates the formation of an aggregated network for the activation of complement-dependent cytolysis and antibody-dependent cell-mediated cytotoxicity, which result in development of granulomatous infections through TNFalpha blockage. These results provide the first experimental model for the interaction of TNFalpha with therapeutic antibodies and offer useful information for antibody optimization by understanding the precise molecular mechanism of TNFalpha inhibition.

Structural basis for treating tumor necrosis factor alpha (TNFalpha)-associated diseases with the therapeutic antibody infliximab., Liang S, Dai J, Hou S, Su L, Zhang D, Guo H, Hu S, Wang H, Rao Z, Guo Y, Lou Z, J Biol Chem. 2013 May 10;288(19):13799-807. doi: 10.1074/jbc.M112.433961. Epub, 2013 Mar 15. PMID:23504311

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]

About this Structure

4g3y is a 3 chain structure with sequence from Gekko coi and Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Liang S, Dai J, Hou S, Su L, Zhang D, Guo H, Hu S, Wang H, Rao Z, Guo Y, Lou Z. Structural basis for treating tumor necrosis factor alpha (TNFalpha)-associated diseases with the therapeutic antibody infliximab. J Biol Chem. 2013 May 10;288(19):13799-807. doi: 10.1074/jbc.M112.433961. Epub, 2013 Mar 15. PMID:23504311 doi:10.1074/jbc.M112.433961
  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

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