We have succeeded in preparing semi-synthesized proteins bound to Sc³⁺ ion which can promote an epoxide ring-opening reaction. The Sc³⁺ binding site was created on the surface of [(gp5βf)₃]₂ (N. Yokoi et al., Small, 2010, 6, 1873) by introducing a cysteine residue for conjugation of a bpy moiety using a thiol–maleimide coupling reaction. Three cysteine mutants [(gp5βf_X)₃]₂ (X = G18C, L47C, N51C) were prepared to introduce a bpy in different positions because it had been reported that Sc³⁺ ion can serve as a Lewis-acid catalyst for an epoxide ring-opening reaction upon binding of epoxide to bpy and two –ROH groups. G18C_bpy with Sc³⁺ can accelerate the rate of catalysis of the epoxide ring-opening reaction and has the highest rate of conversion among the three mutants. The value is more than 20 times higher than that of the mixtures of [(gp5βf)₃]₂/2,2′-bipyridine and L-threonine/2,2′-bipyridine. The elevated activity was obtained by the cooperative effect of stabilizing the Sc³⁺ coordination and accumulation of substrates on the protein surface. Thus, we expect that the semi-synthetic approach can provide insights into new rational design of artificial metalloenzymes.