Reexamination of Lead(II) Coordination Preferences in Sulfur-Rich Sites:  Implications for a Critical Mechanism of Lead Poisoning

• Published in: Journal of the American Chemical Society 2005-07, Vol.127 (26), p.9495-9505
• Main Authors: Magyar, John S, Weng, Tsu-Chien, Stern, Charlotte M, Dye, David F, Rous, Brian W, Payne, John C, Bridgewater, Brian M, Mijovilovich, Ana, Parkin, Gerard, Zaleski, Jeffrey M, Penner-Hahn, James E, Godwin, Hilary Arnold
• Format: Article
• Language: English
• Subjects: Binding Sites; Bioinorganic chemistry; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Chemistry; Child; Child, Preschool; Environmental Pollutants - toxicity; Exact sciences and technology; Humans; Inorganic chemistry and origins of life; Lead - chemistry; Lead - metabolism; Lead - pharmacology; Lead Poisoning - metabolism; Medical sciences; Metals and various inorganic compounds; Proteins - chemistry; Proteins - metabolism; Spectrometry, X-Ray Emission; Sulfur - chemistry; Sulfur - metabolism; Toxicology; Zinc - chemistry; Zinc - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0424530

Recent studies suggest that the developmental toxicity associated with childhood lead poisoning may be attributable to interactions of Pb(II) with proteins containing thiol-rich structural zinc-binding sites. Here, we report detailed structural studies of Pb(II) in such sites, providing critical insights into the mechanism by which lead alters the activity of these proteins. X-ray absorption spectroscopy of Pb(II) bound to structural zinc-binding peptides reveals that Pb(II) binds in a three-coordinate Pb(II)-S3 mode, while Zn(II) is known to bind in a four-coordinate mode in these proteins. This Pb(II)-S3 coordination in peptides is consistent with a trigonal pyramidal Pb(II)-S3 model compound previously reported by Bridgewater and Parkin, but it differs from many other reports in the small molecule literature which have suggested Pb(II)-S4 as a preferred coordination mode for lead. Reexamination of the published structures of these “Pb(II)-S4” compounds reveals that, in almost all cases, the coordination number of Pb is actually 5, 6, or 8. The results reported herein combined with this new review of published structures suggest that lead prefers to avoid four-coordination in sulfur-rich sites, binding instead as trigonal pyramidal Pb(II)-S3 or as Pb(II)-S5 - 8. In the case of structural zinc-binding protein sites, the observation that lead binds in a three-coordinate mode, and in a geometry that is fundamentally different from the natural coordination of zinc in these sites, explains why lead disrupts the structure of these peptides and thus provides the first detailed molecular understanding of the developmental toxicity of lead.