Ellucidation of the Zinc-Finger Motif as a Target for Heavy-Metal Perturbations

Probing a Homoleptic PbS3 Coordination Environment in a Designed Peptide Using 207Pb NMR Spectroscopy: Implications for Understanding the Molecular Basis of Lead Toxicity

“…The presence of a characteristic ligand-to-metal charge-transfer (LMCT) band at about 345 nm (ε ≈ 3500Lmol −1 cm −1 ) is indicative of PbS 3 in a trigonal pyramidal geometry. Recent EXAFS studies by Matzapetakis et al identified a threecoordinate Pb 2+ site in Pb(TRIL16C) 3 − with Pb-S scatters at 2.63 Å. Similar results have been reported by Giedroc and co-workers for the preference of Pb 2+ for a PbS 3 coordination environment in the metalloregulatory protein CadC.…”

“…Lead, which is found in paint and soil, causes toxicity by several possible mechanisms. Pb 2+ interacts with several zinc enzymes or proteins (such as carbonic anhydrase, acetylcholine esterase, Cys 2 His 2 "zinc-finger" proteins, and acid phophatases) [2,3] and calcium ion binding proteins (calmodulin, calbindin, and troponin C).[4] Inhibition of protein function is induced by alternative coordination number and structural preferences. [5,6] Pb 2+ is a chemically interesting toxin in that it can replace calcium and sometimes zinc in "hard" active sites that are oxygen/nitrogen rich; it can also attack softer ligands, such as all-sulfur-containing zinc ion coordination sites.…”

“…Lead, which is found in paint and soil, causes toxicity by several possible mechanisms. Pb 2+ interacts with several zinc enzymes or proteins (such as carbonic anhydrase, acetylcholine esterase, Cys 2 His 2 "zinc-finger" proteins, and acid phophatases) [2,3] and calcium ion binding proteins (calmodulin, calbindin, and troponin C).…”

“…[22][23][24][26][27][28] The 207 Pb NMR signal for the thiol-rich binding sites should be shifted further downfield than that of oxygen-and nitrogen-rich calcium-binding sites. Thus, we can distinguish PbS 3 versus PbS 3 O coordination environments very easily by using 207 Pb NMR. [22] The coordination number and geometry of the Pb 2+ ion can also be examined.…”

“…[22] The coordination number and geometry of the Pb 2+ ion can also be examined. [29] Dean, Payne, Christou, and their co-workers have synthesized [Ph 4 As] [Pb(SPh) 3 ] and characterized complexes in non-aqueous media using 207 Pb NMR spectroscopy. [30][31][32] Despite these studies, no significant advancement of 207 Pb NMR has been accomplished to explore the thiolate-rich proteins scaffolds.…”