Role of metal ions in ligand–receptor interaction: Insights from structural studies

Experimental data indicate that metal ions such as Na(+), Ca(2+) and Mg(2+), which are present in millimolar concentrations in the extracellular environment, modulate binding of ligands to plasma membrane receptors. Here, we briefly review structural studies that demonstrate that various types of ligands, including peptide hormones and drugs, bind metal ions, in particular Ca(2+), in the lipid milieu. We propose that the metal ion-bound forms of ligands represent their bioactive conformations. With a view to understanding the mechanism of modulation of ligand-receptor interactions by metal ions, we have computed a homology model of the mu-opioid receptor, a G protein-coupled receptor (GPCR), and performed docking of specific agonist and antagonist ligands in the receptor. This resulted in the formation of a ligand-metal ion-receptor (ternary) complex which accounted for the data on the structure-activity relationships of ligands and mutation data on the receptor. Based on experimental and modeling data, we have proposed a general mechanism of activation of GPCRs by their corresponding ligands wherein metal ions play a pivotal role. Studies on overexpressed segments of mu-receptor are in progress to verify the above proposal.