Zinc-finger and other zinc-structural protein domains (ZnF) (ZnF)

Zinc-finger and other zinc-structural protein domains are ubiquitous structural motifs characterized by the coordination of one or more zinc ions by cysteine and histidine residues, which stabilizes the protein's functional fold (Klug, 2010). These domains are found in approximately 3% of the human genome and are critical for diverse biological processes, including DNA recognition, RNA binding, and protein-protein interactions (Cassandrier et al., 2021). In a therapeutic context, these motifs are often targeted in viral proteins, such as the HIV-1 nucleocapsid protein, and in oncogenic transcription factors where they mediate DNA binding (Rice et al., 1995). Drugs targeting these domains, known as zinc ejectors, typically function by oxidizing or covalently modifying the coordinating sulfur atoms of cysteine residues, leading to the release of the zinc ion and subsequent loss of the protein's three-dimensional structure and function (Pace & Weerapana, 2014). While promising, targeting these domains presents significant challenges due to the high risk of off-target effects across the vast number of zinc-finger-containing proteins in the human body (Wuthrich, 2000). Consequently, current research focuses on developing site-specific ejectors or targeting unique pockets adjacent to the zinc-binding site to improve selectivity (Maret, 2013).

Other names

Zinc finger motifZinc-binding domainZn-fingerZinc-coordinated domain

Zinc ejection through the chemical modification (oxidation or alkylation) of zinc-coordinating cysteine residues, resulting in the collapse of the domain's tertiary structure and loss of biological activity (Rice et al., 1995; Pace & Weerapana, 2014).