Zinc-thiolate cluster

Zinc-thiolate clusters are specialized structural motifs in proteins where zinc ions are tetrahedrally coordinated by the sulfur atoms of cysteine residues (Maret, 2017, doi:10.3390/ijms18102117). These clusters are most notably found in metallothioneins, where they serve as a dynamic reservoir for zinc ions and provide protection against heavy metal toxicity and oxidative stress (Sutherland & Stillman, 2011, doi:10.1039/c1mt00067g). Beyond storage, these clusters act as redox-sensitive switches; the oxidation of thiolate ligands triggers the release of zinc, which then acts as a secondary messenger in various signaling pathways (Knipp et al., 2007, doi:10.1021/ja073359+). In medicine, zinc-thiolate clusters are significant because they can react with and sequester metal-based drugs like cisplatin, contributing to drug resistance in cancer (Blindauer, 2013, doi:10.3390/genes4020192). Conversely, they are targeted by gold-based compounds and other electrophiles to disrupt the function of specific zinc-containing proteins involved in disease progression.

Other names

Zinc-sulfur clusterZn-S clusterMetallothionein clusterZn-thiolate motif

Drugs typically interact with zinc-thiolate clusters through metal displacement (transmetallation), covalent modification of the thiolate ligands (alkylation or oxidation), or competitive chelation, leading to the release of zinc ions and loss of protein structural integrity or function (Maret, 2017, doi:10.3390/ijms18102117).