Metal coordination in metalloproteins

Metal coordination in metalloproteins refers to the essential interaction between metal ions—such as zinc, iron, copper, or magnesium—and specific amino acid residues or prosthetic groups within a protein structure. Approximately one-third to one-half of the human proteome consists of metalloproteins, where these ions fulfill critical roles in catalysis, structural stability (e.g., zinc fingers), and electron transfer processes (Chen et al., 2018; Waldron & Robinson, 2009). In many enzymes, the metal ion serves as a Lewis acid to facilitate biochemical reactions or acts as a reversible oxygen carrier, as seen in hemoglobin. Many therapeutic agents are designed to target these metallocenters; for instance, HDAC inhibitors like vorinostat utilize a hydroxamate group to coordinate with the catalytic zinc ion, effectively blocking enzymatic activity (Adamek et al., 2018). Dysregulation of metal coordination and systemic metal homeostasis is implicated in diverse pathologies, including neurodegenerative diseases like Alzheimer's, various cancers, and metal-overload disorders like Wilson's disease. Consequently, targeting or modulating these metal-binding sites represents a major focus in medicinal inorganic chemistry and drug development.

Other names

Metal-binding siteMetallocenterMetal-ligand coordinationMetalloenzyme active site

Drugs interact with metalloproteins primarily through coordination to the active-site metal ion using metal-binding pharmacophores (MBPs), which displace endogenous ligands or substrates, or by sequestering metal ions via chelation to disrupt protein function.