Structural differences between Pb2+- and Ca2+-binding sites in proteins: implications with respect to toxicity.

Pb(2+) is known to displace physiologically-relevant metal ions in proteins. To investigate potential relationships between Pb(2+)/protein complexes and toxicity, data from the protein data bank were analyzed to compare structural properties of Pb(2+)- and Ca(2+)-binding sites. Results of this analysis reveal that the majority of Pb(2+) sites (77.1%) involve 2-5 binding ligands, compared with 6+/-2 for non-EF-Hand and 7+/-1 for EF-Hand Ca(2+)-binding sites. The mean net negative charge by site (1.7) fell between values noted for non-EF-Hand (1+/-1) and EF-Hand (3+/-1). Oxygen is the dominant ligand for both Pb(2+) and Ca(2+), but Pb(2+) binds predominantly with sidechain Glu (38.4%), which is less prevalent in both non-EF-Hand (10.4%) and EF-Hand (26.6%) Ca(2+)-binding sites. A comparison of binding geometries where Pb(2+) has replaced Ca(2+) in calmodulin (CaM) and Zn(2+) in 5-aminolaevulinic acid dehydratase (ALAD) revealed protein structural changes that appear to be unrelated to ionic displacement. Structural changes observed with CaM may be related to opportunistic binding of Pb(2+) in regions of high electrostatic charge, whereas ALAD may bind multiple Pb(2+) ions in the active site. These results suggest that Pb(2+) adapts to structurally-diverse binding geometries and that opportunistic binding may play an active role in molecular metal toxicity.