Beyond copper: examining the significance of His-mutations in mycobacterial GroEL1 HRCT for Ni(II) complex stability and formation.

Recently, we have studied the coordination chemistry of the Cu(II)-histidine-rich C-terminal tail (HRCT) complex of the mycobacterial GroEL1 protein. The structure of this domain differs significantly compared to the well-known methionine-glycine-rich GroEL chaperonin - it was predicted that mycobacterial GroEL1 could play a significant role in the metal homeostasis of , especially copper. However, we found that this particular domain's pattern also repeats in a number of Ni(II)-binding proteins.

Exploring binding preferences: Cu(II), Ni(II), and Zn(II) complexes of mycobacterial GroEL1 His-rich and Glu/His-rich domains.

Mycobacterial histidine-rich GroEL1 protein significantly differs from the well-known methionine-glycine-rich GroEL chaperonin and most preferably participates in Cu(II) homeostasis. Some GroEL1 proteins, however, do not possess six but only three histidine residues and more acidic residues that can function as binding sites for metal ions. To evaluate the importance of this difference, we examined and compared the properties of GroEL1 His-rich or Glu/His-rich C-terminal domains as ligands for Cu(II), Ni(II), and Zn(II) ions.

Determination of the role of specific amino acids in the binding of Zn(II), Ni(II), and Cu(II) to the active site of the M10 family metallopeptidase.

Metallopeptidases are a group of metal-dependent enzymes that hydrolyze peptide bonds. These enzymes found in Streptococcus pneumoniae assist the pathogen in infecting the host by breaking down host tissues and extracellular matrix proteins. Considering metallopeptidases' significant role in bacterial virulence, inhibiting this enzyme represents a promising avenue for research.

Fe(II), Mn(II), and Zn(II) Binding to the C-Terminal Region of FeoB Protein: An Insight into the Coordination Chemistry and Specificity of the Fe(II) Transporter.

The interactions between two peptide ligands [AcCCAASTTGDCH () and AcRRARSRVDIELLATRKSVSSCCAASTTGDCH ()] derived from the cytoplasmic C-terminal region of FeoB protein and Fe(II), Mn(II), and Zn(II) ions were investigated. The Feo system is regarded as the most important bacterial Fe(II) acquisition system, being one of the key virulence factors, especially in anaerobic conditions. Located in the inner membrane of Gram-negative bacteria, FeoB protein transports Fe(II) from the periplasm to the cytoplasm.

Copper Forms a PPII Helix-Like Structure with the Catalytic Domains of Bacterial Zinc Metalloproteases.

The rapid spread of antibiotic-resistant bacteria continuously raises concerns about the future ineffectiveness of current antimicrobial treatments against infectious diseases. To address this problem, new therapeutic strategies and antimicrobial drugs with unique modes of action are urgently needed. Inhibition of metalloproteases, bacterial virulence factors, is a promising target for the development of antibacterial treatments.

Histidine-Rich C-Terminal Tail of Mycobacterial GroEL1 and Its Copper Complex─The Impact of Point Mutations.

The mycobacterial histidine-rich GroEL1 protein differs significantly compared to the well-known methionine/glycine-rich GroEL chaperonin. It was predicted that mycobacterial GroEL1 can play a significant role in the metal homeostasis of but not, as its analogue, in protein folding. In this paper, we present the properties of the GroEL1 His-rich C-terminus as a ligand for Cu(II) ions.

Bacterial M10 metallopeptidase as a medicinal target - coordination chemistry of possible metal-based inhibition.

is the most frequent cause of fatal bacterial pneumonia infection worldwide. Due to the spreading of antibiotic-resistant pathogens, it is important to search for new therapeutic and prevention strategies against bacterial infections. It is believed that the search for effective inhibitors of bacterial and pathogenic metallopeptidases could be one of the innovative strategies for the design of new antibiotics.

Zn(II) and Cd(II) Complexes of AMT1/MAC1 Homologous Cys/His-Rich Domains: So Similar yet So Different.

Infections caused by species are becoming seriously dangerous and difficult to cure due to their sophisticated mechanisms of resistance. The host organism defends itself from the invader, e.g.

Coordination Properties of the Zinc Domains of BigR4 and SmtB Proteins in Nickel Systems─Designation of Key Donors.

The increasing number of antibiotic-resistant pathogens has become one of the foremost health problems of modern times. One of the most lethal and multidrug-resistant bacteria is (Mtb), which causes tuberculosis (TB). TB continues to engulf health systems due to the significant development of bacterial multidrug-resistant strains.

Sensing of Proteins by ICD Response of Iron(II) Clathrochelates Functionalized by Carboxyalkylsulfide Groups.

Recognition of elements of protein tertiary structure is crucial for biotechnological and biomedical tasks; this makes the development of optical sensors for certain protein surface elements important. Herein, we demonstrated the ability of iron(II) clathrochelates (-) functionalized with mono-, di- and hexa-carboxyalkylsulfide to induce selective circular dichroism (CD) response upon binding to globular proteins. Thus, inherently CD-silent clathrochelates revealed selective inducing of CD spectra when binding to human serum albumin (HSA) (, ), beta-lactoglobuline () and bovine serum albumin (BSA) ().

Zinc(II)-The Overlooked Éminence Grise of Chloroquine's Fight against COVID-19?

Zn(II) is an inhibitor of 's RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores-this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.

Triplet of cysteines - Coordinational riddle?

Polythiol binding of metal ions plays crucial role in the proper functioning of cysteine-rich proteins that are responsible for metal homeostasis and defending processes against metal toxicity (including heavy metals detoxification). The coordination properties of cysteine residues involved in specific sequencional patterns in proteins (like those present in e.g.

Induced CD of iron(ii) clathrochelates: sensing of the structural and conformational alterations of serum albumins.

An ability of inherently achiral macrobicyclic metal complexes iron(ii) clathrochelates to acquire an induced CD (ICD) output in the visible spectral range upon interaction with bovine serum albumin (BSA) was recently discovered. In the present work, the CD-reporting properties of iron(ii) clathrochelates to proteins and the thermodynamic parameters of their binding to albumins are evaluated. It is shown that iron(ii) clathrochelates functionalized by six ribbed carboxyphenylsulfide groups are able to discriminate between serum albumins of relative structure (here human and bovine albumins) by giving distinct ICD spectra.

Pneumococcal histidine triads - involved not only in Zn, but also Ni binding?

Polyhistidine triad proteins, which participate in Zn2+ uptake in Streptococcus pneumoniae, contain multiple copies of the HxxHxH (histidine triad motif) sequence. We focus on three such motifs from one of the most common and well-conserved polyhistidine triad proteins, PhtA, in order to understand their bioinorganic chemistry; particular focus is given to (i) understanding which of the PhtA triads binds Zn2+ with the highest affinity (and why) and (ii) explaining whether Ni2+ (also crucial for bacterial survival and virulence) could potentially outcompete Zn2+ at its native binding site. There is no significant difference in the stability of zinc(ii) complexes with the three studied protein fragments, but one of the nickel(ii)-polyhistidine triads is remarkably stable; we explain why and hypothesize about the biological importance of this finding.

HENRYK - An endless source of metal coordination surprises.

The basic knowledge about biological inorganic chemistry, thermodynamics and metal binding sites of metalloproteins is crucial for the understanding of their metal binding-structure-function relationship. Metal-peptide complexes are useful and commonly used models of metal-enzyme active sites, among which copper and zinc models are one of the most extensively studied. HENRYK is a peptide sequence present in numerous proteins, and serves as a potentially tempting binding site for Cu and Zn.

Zinc Homeostasis at the Bacteria/Host Interface-From Coordination Chemistry to Nutritional Immunity.

Zinc is one of the most important metal nutrients for species from all kingdoms, being a key structural or catalytic component of hundreds of enzymes, crucial for the survival of both pathogenic microorganisms and their hosts. This work is an overview of the homeostasis of zinc in bacteria and humans. It explains the importance of this metal nutrient for pathogens, describes the roles of zinc sensors, regulators, and transporters, and summarizes various uptake systems and different proteins involved in zinc homeostasis-both those used for storage, buffering, and signaling inside the cell and those excreted in order to obtain Zn from the host.

Specificity of the Zn(2+), Cd(2+) and Ni(2+) ion binding sites in the loop domain of the HypA protein.

The zinc binding loop domain of the HypA protein of Helicobacter pylori consists of two CXXC motifs with flanking His residues. These motifs bind metal ions, and thus they are crucial for the functioning of the whole protein. The N-terminal site, where His is separated from CXXC by Ser residue is more effective in binding Zn(2+) and Ni(2+) ions than the C-terminal site, in which His is adjacent to the CXXC motif.

Metal ion mediated transition from random coil to β-sheet and aggregation of Bri2-23, a natural inhibitor of Aβ aggregation.

Furin-dependent maturation of the BRI2 protein generates the Bri2-23 fragment that is able to arrest the aggregation of amyloidβ, the peptide implicated in Alzheimer's disease (AD). Bri2-23 contains cysteines at positions 5 and 22, which are likely to bind to metal ions such as Cu(i). Metal ions may play a role in the etiology of neurodegenerative disorders such as AD, and in this work we explore the metal ion induced folding and aggregation of Bri2-23 using Hg(ii) and Ag(i) as spectroscopic probes with structural and ligand preferences similar to those of Cu(i), while not displaying redox activity under the experimental conditions.

The unusual binding mechanism of Cu(II) ions to the poly-histidyl domain of a peptide found in the venom of an African viper.

Copper complexes of a poly-His/poly-Gly peptide (EDDHHHHHHHHHGVGGGGGGGGGG-NH2), a natural component of a snake venom, were studied by means of both experimental (thermodynamic, spectroscopic and MS) techniques and molecular dynamics (MD) simulations and density functional theory (DFT) calculations. This peptide proved to be an exceptionally effective copper chelator, forming complexes which are thermodynamically more stable than those formed by both the albumin-like ATCUN motif and several other poly-histidine protein fragments. We show that, in a poly-histidine stretch, copper seems to prefer binding to residues separated by one amino acid and that a correlation between an α-helical structure of the predicted complexes and their thermodynamic stability is observed.

The specificity of interaction of Zn(2+), Ni(2+) and Cu(2+) ions with the histidine-rich domain of the TjZNT1 ZIP family transporter.

The Zrt/Irt-like protein (ZIP) family contributes to the metal homeostasis by regulating the transport of divalent metal cations such as Fe(2+), Zn(2+), Mn(2+), Cd(2+) and sometimes even Cu(2+). Most ZIP members have a long variable loop between transmembrane domains (TMDs) III and IV; this region is predicted to be located in the cytoplasm and is postulated to be the metal ion binding site. In this study, we looked at the thermodynamic behavior and coordination chemistry of Zn(2+), Ni(2+) and Cu(2+) complexes with the histidine-rich domain, Ac-(185)RAHAAHHRHSH(195)-NH2 (HRD), from the yeast TjZNT1 protein, located between TMDs III and IV.

Ni(II) binding to the 429-460 peptide fragment from human Toll like receptor (hTLR4): a crucial role for nickel-induced contact allergy?

The FQH431SNLKQMSEFSVFLSLRNLIYLDISH456TH458TR fragment, containing three histidine residues, the conserved H431 and the non-conserved H456 and H458, located from 429 to 460 amino acid residues in the C-terminal portion of human Toll-like-receptor 4 (hTLR4), which is directly activated by nickel, a well known contact allergen, has been tested for Ni(II) binding. The complex formation capability of the 32-amino acid sequence with Ni(II) ions has been followed by potentiometric, UV-Vis, CD, MS and NMR measurements. Ni(II) is able to bind to all three histidines by forming macrocycle complexes at low and physiological pH.

The extracellular loop of IRT1 ZIP protein--the chosen one for zinc?

Zinc complexes with the extracellular loop of IRT1 (iron-regulated transporter 1), a ZIP (ZRT/IRT - Related Protein) family protein from Arabidopsis thaliana, have been studied. This unstructured fragment is responsible for metal selectivity and is located between the II and III transmembrane domains of IRT1. Zinc complexes with the Ac-(95)MHVLPDSFEMLSSICLEENPWHK(117)-NH2 peptide (IRT1), revealed surprisingly high thermodynamic stability.

The zinc-binding fragment of HypA from Helicobacter pylori: a tempting site also for nickel ions.

HypA, a nickel accessory protein from H. pylori, binds a zinc ion in it's structural site, a loop with two conserved CXXC motifs (Ac-ELECKDCSHVFKPNALDYGVCEKCHS-NH(2)). There are at least three hypotheses on the binding mode of this ion.

Polythiol binding to biologically relevant metal ions.

The coordination properties of three peptides with CXXC motif: Ac-GCASCDNCRACKK-NH(2), Ac-GCASCDNCRAAKK-NH(2) and Ac-GCASCDNARAAKK-NH(2) as donors of four, three and two thiol ligands for Ni(2+),Cd(2+), Zn(2+) and Bi(3+) were studied by potentiometric titrations, UV-Vis and CD spectra measurements. Since the stability of the complexes is closely connected with the amount of the metal-bound cysteine sulfurs, competition plots of the complexes of peptides with 2, 3 and 4 cysteines further prove the involvement of all thiols in the metal ion binding. Furthermore, the sulfur-bound zinc complexes appear to be much more stable than the sulfur-bound nickel ones.