The structure of mouse tumour-necrosis factor at 1.4 angstrom resolution: towards modulation of its selectivity and trimerization

The 1.4 Angstrom resolution structure of recombinant mouse tumour-necrosis factor or (mTNF) at 100 K has been determined. The crystals are triclinic, space group P1, with unit-cell parameters a = 48.06, b = 48.18, c = 51.01 A ngstrom, alpha = 114.8, beta = 103.6, gamma = 91.1 degrees. The structure w as refined to a final crystallographic R value of 19.7% (R-free = 23.3%), i ncluding 3477 protein atoms, one 2-propanol molecule, one Tris molecule and 240 water molecules Throughout the crystal lattice, the trimers are differ ently packed compared with human TNF, which was crystallized in the tetrago nal space group P4(1)2(1)2 and refined to 2.6 Angstrom resolution. The stru ctures of mTNF and human TNF are very similar, diverging mainly in regions that are either flexible and/or involved in crystal packing. Some loops in mTNF which contain residues important for receptor binding are better resol ved than in human TNF, such as the surface-exposed loops 30-34 and 144-147, which are also important for receptor specificity. Compared with human TNF s, the channel formed by the three monomers in mTNF is narrower. One 2-prop anol molecule trapped in the trimeric channel could be a lead compound for the design of TNF inhibitors.