Structures of Silver Fingers and a Pathway to Their Genotoxicity

Recently, we demonstrated that Ag^I can directly replace Zn^II in zinc fingers (ZFs). The cooperative binding of Ag^I to ZFs leads to a thermodynamically irreversible formation of silver clusters destroying the native ZF structure. Thus, a reported loss of biological function of ZF proteins is a likely consequence of such replacement. Here, we report an X-ray absorption spectroscopy (XAS) study of Ag_n S_n clusters formed in ZFs to probe their structural features. Selective probing of the local environment around Ag^I by XAS showed the predominance of digonal Ag^I coordination to two sulfur donors, coordinated with an average Ag-S distance at 2.41 Å. No Ag-N bonds were present. A mixed AgS₂ /AgS₃ geometry was found solely in the CCCH Ag^I -ZF. We also show that cooperative replacement of Zn^II ions with the studied Ag₂ S₂ clusters occurred in a three-ZF transcription factor protein 1MEY#, leading to a dissociation of 1MEY# from the complex with its cognate DNA.