1,721,112 research outputs found
Medicinal Inorganic Chemistry: Identification of New Targets in Drug Discovery
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Derivati di carnosina, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono
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Nerve growth factor peptides bind copper(Ii) with high affinity: A thermodynamic approach to unveil overlooked neurotrophin roles
No full textNerve growth factor (NGF) is a protein essential to neurons survival, which interacts with its receptor as a non‐covalent dimer. Peptides belonging to NGF N‐terminal domain are able to mimic the activity of the whole protein. Such activity is affected by the presence of copper ions. The metal is released in the synaptic cleft where proteins, not yet identified, may bind and transfer to human copper transporter 1 (hCtr1), for copper uptake in neurons. The measurements of the stability constants of copper complexes formed by amyloid beta and hCtr1 peptide fragments suggest that beta‐amyloid (Aβ) can perform this task. In this work, the stability constant values of copper complex species formed with the dimeric form of N‐terminal domain, sequence 1–15 of the protein, were determined by means of potentiometric measurements. At physiological pH, NGF peptides bind one equivalent of copper ion with higher affinity of Aβ and lower than hCtr1 peptide frag-ments. Therefore, in the synaptic cleft, NGF may act as a potential copper chelating molecule, ion-ophore or chaperone for hCtr1 for metal uptake. Copper dyshomeostasis and mild acidic environment may modify the balance between metal, NGF, and Aβ, with consequences on the metal cellular uptake and therefore be among causes of the Alzheimer’s disease onset
Evolutionary Implications of Metal Binding Features in Different Species’ Prion Protein: An Inorganic Point of View
Full text linkPrion disorders are a group of fatal neurodegenerative conditions of mammals. The key molecular event in the pathogenesis of such diseases is the conformational conversion of prion protein, PrPC, into a misfolded form rich in β-sheet structure, PrPSc, but the detailed mechanistic aspects of prion protein conversion remain enigmatic. There is uncertainty on the precise physiological function of PrPC in healthy individuals. Several evidences support the notion of its role in copper homeostasis. PrPC binds Cu2+ mainly through a domain composed by four to five repeats of eight amino acids. In addition to mammals, PrP homologues have also been identified in birds, reptiles, amphibians and fish. The globular domain of protein is retained in the different species, suggesting that the protein carries out an essential common function. However, the comparison of amino acid sequences indicates that prion protein has evolved differently in each vertebrate class. The primary sequences are strongly conserved in each group, but these exhibit a low similarity with those of mammals. The N-terminal domain of different prions shows tandem amino acid repeats with an increasing amount of histidine residues going from amphibians to mammals. The difference in the sequence affects the number of copper binding sites, the affinity and the coordination environment of metal ions, suggesting that the involvement of prion in metal homeostasis may be a specific characteristic of mammalian prion protein. In this review, we describe the similarities and the differences in the metal binding of different species’ prion protein, as revealed by studies carried out on the entire protein and related peptide fragments
Neuroprotection against excitotoxic death by copper complexes of carnosine and its monofunctionalized cyclodextrin derivative
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