Evidence for a direct Cu-Cu bond in the CuA center of cytochrome oxidase is reported. Simulation of the X-ray absorption spectrum of a recombinant CuA-binding domain of Bacillus subtilis cytochrome oxidase, and comparison with a structurally characterized directly-bonding Cu(1.5)…Cu(1.5) inorganic complex, suggests that a Cu-Cu interaction of 2.5 ± 0.1 Å together with a short 2.2 Å Cu-S interaction may be present in the CuA site. In light of these data, previous interpretations of the EXAFS of a number of cytochrome oxidase and nitrous oxide reductase enzymes which modeled the 2.6 Å interaction as a long Cu-S(methionine) bond are possibly incorrect. A structural model based on the new data is presented which suggests that the CuA sites in cytochrome oxidase and N2O reductase are likely composed of a pair of modified type 1 copper centers with one histidine, one cysteine, and one weakly bound ligand (Met and/or Gln) joined by a Cu-Cu bond.
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