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
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, USA.
J Am Chem Soc. 2005 Jul 6;127(26):9495-505. 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)-S(3) 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.
最近的研究表明,与儿童铅中毒相关的发育毒性可能归因于Pb(II)与含有富含硫醇的结构锌结合位点的蛋白质之间的相互作用。在此,我们报告了此类位点中Pb(II)的详细结构研究,为铅改变这些蛋白质活性的机制提供了关键见解。结合到结构锌结合肽上的Pb(II)的X射线吸收光谱表明,Pb(II)以三配位的Pb(II)-S(3)模式结合,而众所周知Zn(II)在这些蛋白质中以四配位模式结合。肽中的这种Pb(II)-S(3)配位与Bridgewater和Parkin先前报道的三角锥型Pb(II)-S(3)模型化合物一致,但与小分子文献中的许多其他报道不同,后者表明Pb(II)-S(4)是铅的首选配位模式。对这些“Pb(II)-S(4)”化合物已发表结构的重新审视表明,在几乎所有情况下,Pb的配位数实际上是5、6或8。本文报道的结果与对已发表结构的这一新综述相结合表明,铅在富含硫的位点中倾向于避免四配位,而是以三角锥型Pb(II)-S(3)或Pb(II)-S(5 - 8)的形式结合。在结构锌结合蛋白位点的情况下,观察到铅以三配位模式结合,且其几何结构与这些位点中锌的天然配位根本不同,这解释了为什么铅会破坏这些肽的结构,从而首次对铅的发育毒性提供了详细的分子理解。