The toxicity of heavy metals, which is associated with the high affinity of the metals for thiolate rich proteins, constitutes a problem worldwide. However, despite this tremendous toxicity concern, the binding mode of AsIII and PbII to proteins is poorly understood. To clarify the requirements for toxic metal binding to metalloregulatory sensor proteins such as AsIII in ArsR/ArsD and PbII in PbrR or replacing ZnII in d-aminolevulinc acid dehydratase (ALAD), we have employed computational and experimental methods examining the binding of these heavy metals to designed peptide models. The computational results show that the mode of coordination of AsIII and PbII is greatly influenced by the steric bulk within the second coordination environment of the metal. The proposed basis of this selectivity is the large size of the ion and, most important, the influence of the stereochemically active lone pair in hemidirected complexes of the metal ion as being crucial. The experimental data show that switching a bulky leucine layer above the metal binding site by a smaller alanine residue enhances the PbII binding affinity by a factor of five, thus supporting experimentally the hypothesis of lone pair steric hindrance. These complementary approaches demonstrate the potential importance of a stereochemically active lone pair as a metal recognition mode in proteins and, specifically, how the second coordination sphere environment affects the affinity and selectivity of protein targets by certain toxic ions

Zampella, G., Neupane, K., DE GIOIA, L., Pecoraro, V. (2012). The Importance of Stereochemically Active Lone Pairs For Influencing PbII and AsIII Protein Binding. CHEMISTRY-A EUROPEAN JOURNAL, 18(7), 2040-2050 [10.1002/chem.201102786].

The Importance of Stereochemically Active Lone Pairs For Influencing PbII and AsIII Protein Binding

ZAMPELLA, GIUSEPPE
;
DE GIOIA, LUCA;
2012

Abstract

The toxicity of heavy metals, which is associated with the high affinity of the metals for thiolate rich proteins, constitutes a problem worldwide. However, despite this tremendous toxicity concern, the binding mode of AsIII and PbII to proteins is poorly understood. To clarify the requirements for toxic metal binding to metalloregulatory sensor proteins such as AsIII in ArsR/ArsD and PbII in PbrR or replacing ZnII in d-aminolevulinc acid dehydratase (ALAD), we have employed computational and experimental methods examining the binding of these heavy metals to designed peptide models. The computational results show that the mode of coordination of AsIII and PbII is greatly influenced by the steric bulk within the second coordination environment of the metal. The proposed basis of this selectivity is the large size of the ion and, most important, the influence of the stereochemically active lone pair in hemidirected complexes of the metal ion as being crucial. The experimental data show that switching a bulky leucine layer above the metal binding site by a smaller alanine residue enhances the PbII binding affinity by a factor of five, thus supporting experimentally the hypothesis of lone pair steric hindrance. These complementary approaches demonstrate the potential importance of a stereochemically active lone pair as a metal recognition mode in proteins and, specifically, how the second coordination sphere environment affects the affinity and selectivity of protein targets by certain toxic ions
Articolo in rivista - Articolo scientifico
Arsenic; Heavy Metal Toxicity; Lead; Lone Pairs; Selective Binding; Dft; 3-Stranded Coiled Coils; Stereognostic Coordination Chemistry; Merr Metalloregulatory Protein; Lead Sequestering Agents; Metal-Ion Coordination; Interactions Stabilize; Structural Characteristics; Ralstonia-Metallidurans; Designed Peptides; Biliary-Excretion
English
2012
18
7
2040
2050
none
Zampella, G., Neupane, K., DE GIOIA, L., Pecoraro, V. (2012). The Importance of Stereochemically Active Lone Pairs For Influencing PbII and AsIII Protein Binding. CHEMISTRY-A EUROPEAN JOURNAL, 18(7), 2040-2050 [10.1002/chem.201102786].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/44678
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