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

Magyar, John S. and Weng, Tsu-Chien and Stern, Charlotte M. and Dye, David F. and Rous, Brian W. and Payne, John C. and Bridgewater, Brian M. and Mijovilovich, Ana and Parkin, Gerard and Zaleski, Jeffrey M. and Penner-Hahn, James E. and Godwin, Hilary Arnold (2005) Reexamination of Lead(II) Coordination Preferences in Sulfur-Rich Sites: Implications for a Critical Mechanism of Lead Poisoning. Journal of the American Chemical Society, 127 (26). pp. 9495-9505. ISSN 0002-7863. doi:10.1021/ja0424530.

[img] PDF (Crystal data and structure refinement for 2 (Table S1), comparison of key XAS and crystal structure distances for 2 (Table S2), XANES and EXAFS spectra for all Pb−peptide complexes measured (Figures S1, S2), fits for the CP−CCXX EXAFS data (Figure S3), UV) - Supplemental Material
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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)-S_3 coordination in peptides is consistent with a trigonal pyramidal Pb(II)-S_3 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)-S_4 as a preferred coordination mode for lead. Reexamination of the published structures of these “Pb(II)-S_4” 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)-S_3 or as Pb(II)-S_(5-8). 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.

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Magyar, John S.0000-0002-3586-8286
Additional Information:© 2005 American Chemical Society. Received December 15, 2004; Revised Manuscript Received April 29, 2005. Publication Date (Web): June 9, 2005. We acknowledge J. T. Rijssenbeek and H. B. Gray for helpful discussions. We thank the National Institutes of Health (GM-58183 to H.A.G., GM-38047 to J.P.H., and GM-46502 to G.P.) and the National Science Foundation (CHE-9875341 and CHE-9810378 to H.A.G.) for support of this research. Synchrotron measurements were made at SSRL, which is supported by the NIH Research Resource program and the U.S. DOE. H.A.G. acknowledges additional support from the Burroughs Wellcome Fund, the Camille and Henry Dreyfus Foundation, and the Sloan Foundation. J.S.M. acknowledges support from an NIH Institutional NRSA Training Grant in Molecular Biophysics (GM-08382) and from the Institute for Environmental Catalysis at Northwestern University, funded by the NSF and U.S. DOE (NSF CHE-9810378). G.P. also acknowledges support from the NSF and U.S. DOE via the Columbia University Environmental Molecular Sciences Institute (NSF CHE-9810367).
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Department of Energy (DOE)UNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Camille and Henry Dreyfus FoundationUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
NIH Predoctoral FellowshipGM-08382
Issue or Number:26
Record Number:CaltechAUTHORS:20170427-083925553
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Official Citation:Reexamination of Lead(II) Coordination Preferences in Sulfur-Rich Sites:  Implications for a Critical Mechanism of Lead Poisoning John S. Magyar, Tsu-Chien Weng, Charlotte M. Stern, David F. Dye, Brian W. Rous, John C. Payne, Brian M. Bridgewater, Ana Mijovilovich, Gerard Parkin, Jeffrey M. Zaleski, James E. Penner-Hahn, and Hilary Arnold Godwin Journal of the American Chemical Society 2005 127 (26), 9495-9505 DOI: 10.1021/ja0424530
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:76982
Deposited By: Tony Diaz
Deposited On:27 Apr 2017 16:28
Last Modified:15 Nov 2021 17:04

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