The mitochondrial enzyme cytochrome c oxidase catalyzes the reduction of molecular oxygen in the critical step of oxidative phosphorylation that links the oxidation of food consumed to ATP production in cells. The enzyme catalyzes the reduction of oxygen at two vastly different rates that are thought to be linked to two different conformations but the conformation of the "fast enzyme" remains obscure. In this study, we demonstrated how oxygen binding at haem a3 could trigger long-distance conformational changes and then simulated a conformational change in an eight-residue loop near the enzyme's substrate (cytochrome c) binding site. We then used this modified cytochrome c oxidase (COX) to simulate a stable COX-cytochrome c enzyme-substrate (ES) complex. Compared to ES complexes formed in the absence of the conformation change, the distance between the redox centers of the two proteins was reduced by half and instead of nine, only four COX amino acid residues were found along the axis linking the electron entry point and the CuA redox center of COX: We proposed that intramolecular electron transfer in COX occurs via a charge/hydrogen relay system involving these four residues. We suggest that the conformational change and resulting shortened electron pathway are features of fast-acting COX.