PDB 2AZ5 deposited: 2005-09-09 modified: 2009-02-24
Title Crystal Structure of TNF-alpha with a small molecule inhibitor
Authors Braisted, A.C., Cachero, T.G., Cancilla, M.T., Choong, I.C., Cruz, L.A., Cunningham, B.C., Day, E.S., Eldredge, J.K., Farrington, G., Flanagan, W.M., Friedman, J.E., Fung, A.D., He, M.M., Lugovskoy, A.A., Miller, S.K., Oslob, J.D., Smith, A.S., Wang, J., Whitty, A., Yoburn, J.C.
Structure factors resolution 2.1 rfactor 0.22 rfree 0.278
DPI 0.76 theoretical min: 0.25

We have identified a small-molecule inhibitor of tumor necrosis factor alpha (TNF-alpha) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-alpha activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-alpha subunits.

Science 2005 Nov; 310(5750):1022-1025 doi:10.1126/science.1116304

Cross References
Database source Identifier Description
PubMed 16284179 SCIEAS
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2AZ5/1 2AZ5 1 tetramer 0 4 2 4114