COMPARISON OF THE CRYSTAL-STRUCTURES OF GENETICALLY ENGINEERED HUMAN MANGANESE SUPEROXIDE-DISMUTASE AND MANGANESE SUPEROXIDE-DISMUTASE FROMTHERMUS-THERMOPHILUS - DIFFERENCES IN DIMER DIMER INTERACTION

The three-dimensional X-ray structure of a recombinant human mitochond rial manganese superoxide dismutase (MnSOD) (chain length 198 residues ) was determined by the method of molecular replacement using the rela ted structure of MnSOD from Thermus thermophilus as a search model. Th is tetrameric human MnSOD crystallizes in space group P2(1)2(1)2 with a dimer in the asymmetric unit (Wagner, U.G., Werber, M.M., Beck, Y., Hartman, J.R., Frolow, F., & Sussman, J.L., 1989, J. Mol. Biol. 206, 7 87-788). Refinement of the protein structure (3,148 atoms with Mn and no solvents), with restraints maintaining noncrystallographic symmetry , converged at an R-factor of 0.207 using all data from 8.0 to 3.2 ang strom resolution and group thermal parameters. The monomer-monomer int eractions typical of bacterial Fe- and Mn-containing SODs are retained in the human enzyme, but the dimer-dimer interactions that form the t etramer are very different from those found in the structure of MnSOD from T. thermophilus. In human MnSOD one of the dimers is rotated by 8 4-degrees relative to its equivalent in the thermophile enzyme. As a r esult the monomers are arranged in an approximately tetrahedral array, the dimer-dimer packing is more intimate than observed in the bacteri al MnSOD from T thermophilus, and the dimers interdigitate. The metal- ligand interactions, determined by refinement and verified by computat ion of omit maps, are identical to those observed in T thermophilus Mn SOD.