Factor Inhibiting Hypoxia–Inducible Factor (FIH) is an α-ketoglutarate (αKG) dependent enzyme which catalyzes hydroxylation of residue Asn803 in the C-terminal transactivation domain (CAD) of hypoxia–inducible factor 1α (HIF-1α) and plays an important role in cellular oxygen sensing and hypoxic response. Circular dichroism (CD), magnetic circular dichroism (MCD) and variable–temperature, variable–field (VTVH) MCD spectroscopies are used to determine the geometric and electronic structures of FIH in its (FeII), (FeII/αKG) and (FeII/αKG/CAD) forms. (FeII)FIH and (FeII/αKG)FIH are found to be six-coordinate (6C), whereas (FeII/αKG/CAD)FIH is found to be a 5C/6C mixture. Thus, FIH follows the general mechanistic strategy of nonheme FeII enzymes. Modeling shows that when Arg238 of FIH is removed the facial triad carboxylate binds to FeII in a bidentate mode with concomitant lengthening of the FeII–αKG-carbonyl bond, which would inhibit the O2 reaction. Correlations over α-keto acid-dependent enzymes and with the extradiol dioxygenases shows that members of these families (where both the electron source and O2 bind to FeII) have a second-sphere residue H-bonding to the terminal oxygen of the carboxylate, which stays monodentate. Alternatively, structures of the pterin-dependent and Rieske dioxygenases, which do not have substrate binding to FeII, lack H-bonds to the carboxylate, and thus allow its bidentate coordination which would direct O2 reactivity. Finally, Vis-UV MCD spectra show an unusually high-energy FeII→αKG π* metal-to-ligand charge transfer transition in (FeII/αKG)FIH which is red-shifted upon CAD binding. This red shift indicates formation of H bonds to the αKG that lower the energy of its carbonyl LUMO, activating it for nucleophilic attack by the Fe-O2 intermediate formed along the reaction coordinate.