Structural Biology of Zinc-Binding Proteins and Peptides

Abstract

This review systematizes current data on the structural organization, coordination chemistry, and functional roles of zinc-binding proteins and peptides. The mechanisms by which Zn²⁺ ions participate in homeostasis, enzymatic catalysis, signal transduction, and pathological processes are analyzed. A large dataset of zinc-containing protein structures deposited in the Protein Data Bank was examined. Tetrahedral coordination geometry predominates for zinc ions (over 67% of structures), with more than 92% of coordinating groups represented by residues of Cys, His, Asp, Glu, and water molecules. The most common coordination motifs are Cys₄, Cys₃His, and Cys₂His₂. Zinc ions perform both structural roles (e.g., zinc fingers, metallothioneins) and catalytic functions (including water activation and substrate polarization). The mechanisms of Zn²⁺-dependent enzymes are discussed, including carbonic anhydrases, carboxypeptidase A, superoxide dismutases, alcohol dehydrogenases, alkaline phosphatases, and matrix metalloproteinases. Zinc homeostasis systems (ZIP importers, ZnT exporters, and metallothioneins) and their regulation by transcription factors MTF-1 (in vertebrates) and ZntR (in bacteria) are described. Evidence is reviewed for the modulation of a wide range of membrane receptors by Zn²⁺ ions through multiple mechanisms, including allosteric inhibition or potentiation, stabilization of protein–protein interactions (“zinc clasps”), and ligand binding. A structural classification of zinc fingers is presented, ranging from classical CysHis₂ domains to more complex architectures containing two Zn²⁺ ions. Using the β-amyloid peptide (Aβ) as an example, the role of Zn²⁺ in pathogenic oligomerization is demonstrated, and approaches to inhibit this process are outlined. The conservation of ligand environments combined with variability in zinc coordination numbers provides a balance between rigidity and lability, enabling both structural and catalytic functions. Disruption of zinc homeostasis underlies a range of pathologies, including neurodegenerative diseases, diabetes, immune deficiency, and cancer. This review summarizes key concepts essential for further studies of Zn²⁺ ions in biological systems and for the development of therapeutic strategies based on controlling zinc-dependent biological processes.