Zinc-dependent metalloenzymes and structural zinc-binding proteins

Zinc-dependent metalloenzymes and structural zinc-binding proteins constitute approximately 10% of the human proteome, performing essential roles in catalysis, structural stabilization, and regulation (Maret, 2013, PMID: 23412844). This broad class includes enzymes where zinc acts as a Lewis acid, such as Carbonic Anhydrases and Matrix Metalloproteinases (MMPs), as well as structural motifs like zinc fingers that facilitate DNA binding in transcription factors (Vallee & Auld, 1990, PMID: 2111115). These proteins are implicated in a wide array of pathologies, including cancer metastasis, hypertension, and neurodegeneration, making them significant therapeutic targets (Parkin & Hoffmann, 2003, DOI: 10.1039/B211443C). Pharmacological intervention typically involves small molecules with zinc-binding groups (ZBGs) like hydroxamates, carboxylates, or sulfonamides that coordinate with the metal ion to inhibit activity (Chen et al., 2019, PMID: 31204835). However, the ubiquity of zinc-binding sites across the proteome presents a major challenge for drug selectivity and can lead to off-target toxicity (Bertini et al., 2007, ISBN: 978-1891389436).

Other names

Zinc-binding proteinsZinc metalloproteinsZn-dependent enzymesZinc-dependent proteins

Drugs targeting this class typically function by coordinating a zinc-binding group (ZBG) to the catalytic zinc ion, thereby competitively inhibiting enzymatic activity, or by disrupting the structural integrity of zinc-coordinated motifs like zinc fingers to prevent protein-DNA or protein-protein interactions (Chen et al., 2019, PMID: 31204835).