The Orange Protein (ORP) is a small bacterial protein, of unknown function, that harbors a unique molybdenum/copper (Mo/Cu) heterometallic cluster, [S(2)Mo(VI)S2Cu(I)S(2)Mo(VI)S(2)](3-), noncovalently bound. The apo-ORP is able to promote the formation and stabilization of this cluster, using Cu-II- and (MoS42-)-S-VI salts as starting metallic reagents, to yield a Mo/CuORP that is virtually identical to the native ORP. In this work, we explored the ORP capability of promoting protein-assisted synthesis to prepare novel protein derivatives harboring molybdenum heterometallic clusters containing iron, cobalt, nickel, or cadmium in place of the "central" copper (Mo/Fe-ORP, Mo/Co-ORP, Mo/Ni-ORP, or Mo/Cd-ORP). For that, the previously described protein-assisted synthesis protocol was extended to other metals and the Mo/M-ORP derivatives (M = Cu, Fe, Co, Ni, or Cd) were spectroscopically (UV visible and electron paramagnetic resonance (EPR)) characterized. The Mo/Cu-ORP and Mo/Cd-ORP derivatives are stable under oxic conditions, while the Mo/Fe-ORP, Mo/Co-ORP, and Mo/Ni-ORP derivatives are dioxygen-sensitive and stable only under anoxic conditions. The metal and protein quantification shows the formation of 2Mo:1M:10RP derivatives, and the visible spectra suggest that the expected {S2MoS2MS2MoS2} complexes are formed. The Mo/Cu-ORP, Mo/Co-ORP, and Mo/Cd-ORP are EPR-silent. The Mo/Fe-ORP derivative shows an EPR S = +/- 3/2 signal (E/D approximate to 0.27, g approximate to 5.3, 2.5, and 1.7 for the lower M=+/- 1/2 doublet, and g approximate to 5.7 and 1.7 (1.3 predicted) for the upper M = 3/2 doublet), consistent with the presence of either one S = 5/2 Felll antiferromagnetically coupled to two S = 1/2 Mov or one S = 3/2 Fe' and two S = 0 MoVI ions, in both cases in a tetrahedral geometry. The Mo/Ni-ORP shows an EPR axial S =1/2 signal consistent with either one S =1/2 Ni-I and two S = 0 Mow or one S = 1/2 antiferromagnetically coupled to two S =1/2 Mov ions, in both cases in a square-planar geometry. The Mo/Cu-ORP and Mo/Cd-ORP are described as {Mo-VI-Cu-I-Mo-VI and {Mo-VI-Cd-II- Mo-VI, respectively, while the other derivatives are suggested to exist in at least two possible electronic structures, {Movi MI Mo-VI} {Mo-V-M-III-Mo-V}.