Zinc-dependent enzymes and zinc-finger domains (Zn-proteins)

Zinc-dependent proteins, encompassing both zinc-dependent enzymes and zinc-finger domains, represent a vast and diverse class of molecules essential for numerous physiological processes [6]. Zinc-dependent enzymes, such as matrix metalloproteinases (MMPs), carbonic anhydrases (CAs), and histone deacetylases (HDACs), utilize the Lewis acid properties of the zinc cation to facilitate catalytic reactions involved in metabolism, tissue remodeling, and epigenetic regulation [4, 5, 10]. Zinc-finger domains are among the most common protein motifs in the human genome, primarily functioning as DNA-binding modules in transcription factors to regulate gene expression and maintain genomic integrity [1, 2, 8]. Because of their critical roles in disease pathogenesis, these proteins are major therapeutic targets for conditions including hypertension, glaucoma, cancer, and viral infections [2, 3, 10]. Drugs targeting these proteins often employ zinc-chelating groups, such as hydroxamic acids, or act as molecular glues to induce the degradation of specific zinc-finger transcription factors [10, 11]. However, the ubiquity of zinc-binding motifs across the proteome poses significant challenges for achieving drug selectivity and avoiding systemic toxicity or off-target effects [2, 10].

Other names

Zinc-binding proteinsZinc-metalloproteinsZinc-finger proteinsZinc-dependent metalloenzymes

Inhibition of catalytic activity via zinc chelation or active site blocking; targeted protein degradation via molecular glues; disruption of DNA-binding and protein-protein interactions.