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Matthew R. Mehlenbacher Rahma Elsiesy Rabina Lakha Rhiza Lyne E. Villones Marina Orman Christina L. Vizcarra Gabriele Meloni Dean E. Wilcox Rachel N. Austin 《Chemical science》2022,13(18):5289
Metallothioneins (MTs) are a ubiquitous class of small metal-binding proteins involved in metal homeostasis and detoxification. While known for their high affinity for d10 metal ions, there is a surprising dearth of thermodynamic data on metals binding to MTs. In this study, Zn2+ and Cu+ binding to mammalian metallothionein-3 (MT-3) were quantified at pH 7.4 by isothermal titration calorimetry (ITC). Zn2+ binding was measured by chelation titrations of Zn7MT-3, while Cu+ binding was measured by Zn2+ displacement from Zn7MT-3 with competition from glutathione (GSH). Titrations in multiple buffers enabled a detailed analysis that yielded condition-independent values for the association constant (K) and the change in enthalpy (ΔH) and entropy (ΔS) for these metal ions binding to MT-3. Zn2+ was also chelated from the individual α and β domains of MT-3 to quantify the thermodynamics of inter-domain interactions in metal binding. Comparative titrations of Zn7MT-2 with Cu+ revealed that both MT isoforms have similar Cu+ affinities and binding thermodynamics, indicating that ΔH and ΔS are determined primarily by the conserved Cys residues. Inductively coupled plasma mass spectrometry (ICP-MS) analysis and low temperature luminescence measurements of Cu-replete samples showed that both proteins form two Cu4+–thiolate clusters when Cu+ displaces Zn2+ under physiological conditions. Comparison of the Zn2+ and Cu+ binding thermodynamics reveal that enthalpically-favoured Cu+, which forms Cu4+–thiolate clusters, displaces the entropically-favoured Zn2+. These results provide a detailed thermodynamic analysis of d10 metal binding to these thiolate-rich proteins and quantitative support for, as well as molecular insight into, the role that MT-3 plays in the neuronal chemistry of copper.Metallothioneins (MTs) are a ubiquitous class of small metal-binding proteins involved in metal homeostasis and detoxification. 相似文献
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Rabina Pradhan Vincent M. Groner Kaylaa L. Gutman Zachariah M. Heiden Mark F. Roll James G. Moberly 《Supramolecular chemistry》2020,32(8):466-478
ABSTRACT The straightforward synthesis of redox-active arylazothioformamide (ATF) ligands allows for electronic diversity as to measure the weak-binding interactions of transition metal salts in supramolecular coordination complexes. A small library of para-substituted ATFs was created with varied electronic components to evaluate how electron-donating and electron-withdrawing groups alter binding association constants. Following full characterisation, including single-crystal X-ray diffraction, UV-Vis titration studies were performed using copper(I) salts to assess the Host:Guest binding. Simultaneously, substitutions were evaluated computationally by modelling the Gibbs’ Free Energy change of the rotational barriers from ligand crystal structures to the predicted metal coordinating species and the various complexes. The multi-model association calculations and experimental measurements interplay to help limit error propagations and reliably predict the more accurate binding models. Through a thorough investigation it was found that experimentally, each ligand supports a 2:1 binding model yet may employ unique binding mechanisms to achieve that model. 相似文献
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