In this study, different EPR techniques were applied, supported by computational structure predication, to gain insight into a native protein that is hardly tractable with high-resolution structural biology methods. We conclude that native mammalian HRG acts like a sponge for Cu II (and other divalent metal ions, with Zn II known to play an important regulatory role), using a set of high-affinity binding sites involving histidine-coordination of the metal ions and a much larger number of loweraffinity binding sites not involving histidine residues. We further conclude that the predicted disordered PRR1-HRR-PRR2 region of HRG allows for a gradual and flexible adaptation of structural features dependent on metal ion loading, as identified by EPR studying the general topology of HRG metal ion binding sites and their chemical environment. Further studies are required to characterise these induced HRR structural features in the context of effector binding and local metal ion concentration. Ideally, a recombinant expression system for HRG could be established, allowing specific modifications and isotope labelling.