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

摘要

Pb2+ is known to displace physiologically-relevant metal ions in proteins. To investigate potential relationships between Pb2+ protein complexes and toxicity, data from the protein data bank were analyzed to compare structural properties of Pb2+- and Ca2+-binding sites. Results of this analysis reveal that the majority of Pb2+ sites (77.1%) involve 2-5 binding ligands, compared with 6 +/- 2 for non-EF-Hand and 7 +/- 1 for EF-Hand Ca2+-binding sites. The mean net negative charge by site (1.7) fell between values noted for non-EF-Hand (11 1) and EF-Hand (3 1). Oxygen is the dominant ligand for both Ph2+ and Ca2+, but Pb2+ binds predominantly with sidechain Glu (38.4%), which is less prevalent in both non-EF-Hand (10.4%) and EF-Hand (26.6%) Ca2+ -binding sites. A comparison of binding geometries where Pb2+ has replaced Ca2+ in calmodulin (CaM) and Zn2+ 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 Pb2+ in regions of high electrostatic charge, whereas ALAD may bind multiple Pb2+ ions in the active site. These results suggest that Pb2+ adapts to structurally-diverse binding geometries and that opportunistic binding may play an active role in molecular metal toxicity.(c) 2008 Elsevier Inc. All rights reserved.