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Special Issue "Interaction between Metal Compounds and Proteins 2.0"

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Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warszawa, Poland
Interests: bioinorganic chemistry; metal ion-protein complexes; metal ion–peptide complexes; posttranslational modifications; enzymology; protein dynamics; oxidative stress

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Dear Colleagues,

Metal ions play many roles, ranging from physiological stabilization of native protein structure, through pathological induction of improper structure and aggregation of proteins or peptides, to structuring of the organic scaffold in metallodrugs. Thus, a thorough knowledge of the interaction of metal compounds with proteins is crucial for our understanding of physiology and pathology and allows us to design effective therapeutics or research tools.

Quantitative descriptions of binding strength, structural characterizations, and molecular simulations of metal compound–protein interactions are highly welcome. Research on biological and biochemical/biophysical activities of such complexes is also within the scope of this Special Issue. We encourage researchers working on these topics to submit research articles, communications, or reviews for this issue.

Dr. Tomasz Frączyk
Guest Editor

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Open AccessCommunication

Chelator PBT2 Forms a Ternary Cu²⁺ Complex with β-Amyloid That Has High Stability but Low Specificity

Simon C. Drew

Int. J. Mol. Sci. 2023, 24(11), 9267; https://doi.org/10.3390/ijms24119267 - 25 May 2023

Viewed by 549

Abstract

The metal chelator PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) acts as a terdentate ligand capable of forming binary and ternary Cu²⁺ complexes. It was clinically trialed as an Alzheimer’s disease (AD) therapy but failed to progress beyond phase II. The β-amyloid (Aβ) peptide associated with AD was recently concluded to form a unique Cu(Aβ) complex that is inaccessible to PBT2. Herein, it is shown that the species ascribed to this binary Cu(Aβ) complex in fact corresponds to ternary Cu(PBT2)N_Im^Aβ complexes formed by the anchoring of Cu(PBT2) on imine nitrogen (N_Im) donors of His side chains. The primary site of ternary complex formation is His6, with a conditional stepwise formation constant at pH 7.4 (

K_{c}

[M⁻¹]) of log

K^{c}

= 6.4 ± 0.1, and a second site is supplied by His13 or His14 (log

K^{c}

= 4.4 ± 0.1). The stability of Cu(PBT2)N_Im^H13/14 is comparable with that of the simplest Cu(PBT2)N_Im complexes involving the N_Im coordination of free imidazole (log

K^{c}

= 4.22 ± 0.09) and histamine (log

K^{c}

= 4.00 ± 0.05). The 100-fold larger formation constant for Cu(PBT2)N_Im^H6 indicates that outer-sphere ligand–peptide interactions strongly stabilize its structure. Despite the relatively high stability of Cu(PBT2)N_Im^H6, PBT2 is a promiscuous chelator capable of forming a ternary Cu(PBT2)N_Im complex with any ligand containing an N_Im donor. These ligands include histamine, L-His, and ubiquitous His side chains of peptides and proteins in the extracellular milieu, whose combined effect should outweigh that of a single Cu(PBT2)N_Im^H6 complex regardless of its stability. We therefore conclude that PBT2 is capable of accessing Cu(Aβ) complexes with high stability but low specificity. The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)N_Im and analogous Zn(PBT2)N_Im complexes may be relevant to its antimicrobial properties. Full article

(This article belongs to the Special Issue Interaction between Metal Compounds and Proteins 2.0)

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Open AccessArticle

Zn²⁺ and Cu²⁺ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein

Elzbieta Gumienna-Kontecka

Serenella Medici

and

Maria Antonietta Zoroddu

Int. J. Mol. Sci. 2023, 24(11), 9202; https://doi.org/10.3390/ijms24119202 - 24 May 2023

Cited by 1 | Viewed by 1055

Abstract

The spike protein (S) of SARS-CoV-2 is able to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor with a much higher affinity compared to other coronaviruses. The binding interface between the ACE2 receptor and the spike protein plays a critical role in the entry mechanism of the SARS-CoV-2 virus. There are specific amino acids involved in the interaction between the S protein and the ACE2 receptor. This specificity is critical for the virus to establish a systemic infection and cause COVID-19 disease. In the ACE2 receptor, the largest number of amino acids playing a crucial role in the mechanism of interaction and recognition with the S protein is located in the C-terminal part, which represents the main binding region between ACE2 and S. This fragment is abundant in coordination residues such as aspartates, glutamates, and histidine that could be targeted by metal ions. Zn²⁺ ions bind to the ACE2 receptor in its catalytic site and modulate its activity, but it could also contribute to the structural stability of the entire protein. The ability of the human ACE2 receptor to coordinate metal ions, such as Zn²⁺, in the same region where it binds to the S protein could have a crucial impact on the mechanism of recognition and interaction of ACE2–S, with consequences on their binding affinity that deserve to be investigated. To test this possibility, this study aims to characterize the coordination ability of Zn²⁺, and also Cu²⁺ for comparison, with selected peptide models of the ACE2 binding interface using spectroscopic and potentiometric techniques. Full article

(This article belongs to the Special Issue Interaction between Metal Compounds and Proteins 2.0)

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