The high turnover rates of [FeFe]-hydrogenases under mild conditions and at low overpotentials provide a natural blueprint for the design of hydrogen catalysts. However, the unique active site (H-cluster) degrades upon contact with oxygen. The [FeFe]-hydrogenase from Clostridium beijerinckii (CbA5H) is characterized by the flexibility of its protein structure, which allows a conserved cysteine to coordinate to the active site under oxidative conditions. Thereby, intrinsic cofactor degradation induced by dioxygen is minimized. However, the protection from O2 is only partial, and the activity of the enzyme decreases upon each exposure to O2. By using site directed mutagenesis in combination with electrochemistry, ATR-FTIR spectroscopy and molecular dynamics simulations, we show that the kinetics of the conversion between the oxygen protected inactive state (cysteine-bound) and the oxygen-sensitive active state can be accelerated by replacing a surface residue that is very distant from the active site. This sole exchange of a methionine for a glutamate residue leads to an increased resistance of the hydrogenase to dioxygen. With our study we aim to understand how local modifications of the protein structure can have a crucial impact on protein dynamics and how they can control the reactivity of inorganic active sites through outer sphere effects.