title: Structural basis for treating tumor necrosis factor α (TNFα)-associated diseases with the therapeutic antibody infliximab.
abstract: BACKGROUND
  Although infliximab has high efficacy in treating TNFα-associated diseases, the epitope on TNFα remains unclear.
  
  
  RESULTS
  The crystal structure of the TNFα in complex with the infliximab Fab is reported at a resolution of 2.6 Å.
  
  
  CONCLUSIONS
  TNFα E-F loop plays a crucial role in the interaction.
  
  
  CONCLUSIONS
  The structure may lead to understanding the mechanism of mAb anti-TNFα Monoclonal antibody (mAb) drugs have been widely used for treating tumor necrosis factor α (TNFα)-related diseases for over 10 years. Although their action has been hypothesized to depend in part on their ability to bind precursor cell surface TNFα, the precise mechanism and the epitope bound on TNFα remain unclear. In the present work, we report the crystal structure of the infliximab Fab fragment in complex with TNFα at a resolution of 2.6 Å. The key features of the TNFα E-F loop region in this complex distinguish the interaction between infliximab and TNFα from other TNF-receptor structures, revealing the mechanism of TNFα inhibition by overlapping with the TNFα-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 TNFα blockage. These results provide the first experimental model for the interaction of TNFα with therapeutic antibodies and offer useful information for antibody optimization by understanding the precise molecular mechanism of TNFα inhibition.
authors.affiliation: Laboratory of Structural Biology and Ministry of Education Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Shuaiyi
authors.initials: S
authors.lastname: Liang
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Lishu
authors.initials: L
authors.lastname: Su
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Huaizu
authors.initials: H
authors.lastname: Guo
authors.forename: Shi
authors.initials: S
authors.lastname: Hu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D055910:Antibodies, Immobilized / Q000737:chemistry; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D000069285:Infliximab; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D055910:Antibodies, Immobilized; D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab
keywords: Antibodies; Antibody Therapy; Arthritis; Crystal Structure; Drug Action; Infliximab; Mechanism; Tumor Necrosis Factor (TNF)