PDB 4G3Y deposited: 2012-07-15 modified: 2013-08-07
Title Crystal structure of TNF-alpha in complex with Infliximab Fab fragment
Authors Dai, J.X., Guo, H., Guo, Y.J., Hou, S., Hu, S., Liang, S.Y., Lou, Z.Y., Rao, Z., Su, L., Wang, H., Zhang, D.
Structure factors resolution 2.6 rfactor 0.189 rfree 0.2348
DPI 0.99 theoretical min: 0.36

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. CONCLUSION: TNFα E-F loop plays a crucial role in the interaction. SIGNIFICANCE: 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.

J.Biol.Chem. 2013 May; 288(19):13799-13807 doi:10.1074/jbc.M112.433961

Cross References
Database source Identifier Description
PubMed 23504311 JBCHA3
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
4G3Y/1 4G3Y 1 nonamer 0 9 0 12453
4G3Y/2 4G3Y 2 trimer 0 3 0 4151