1,721,158 research outputs found
Recent advances in protein metalation: structural studies
No full textProtein metalation is a process that determines the formation of adducts upon reaction of metal compounds with proteins. Protein metalation plays a crucial role in different fields, determining the mechanism of action and toxicity of metal-based drugs and the basis for the rational design of artificial metalloenzymes and protein-based metallodrug-delivery systems. Recent advances in structural studies unveiling the basis of the metal compounds/protein recognition process are briefly discussed here. The analysis of the structures of Pt, Au, Ru, Re, Pd, Ir, Os, Rh and Pt-As/protein adducts reveals that metal compounds (i) can bind proteinsvianon-covalent interactions orviacoordination to selected residue side chains upon the release of labile ligands; (ii) can undergo reduction/oxidation processes upon protein binding that in turn can lead to changes in the metal coordination sphere and breakdown of the metal compound; (iii) can bind different protein recognition sites with a preference for selected side chains that is governed by hard and soft acids and bases, and with the number and type of binding sites changing over time; and (iv) can retain a certain degree of flexibility and reactivity in the final metal/protein adduct
X-ray structure of bovine heart cytochrome c at high ionic strength
No full textBovine heart cytochrome c (bCyt c) is an extensively studied hemoprotein of only 104 residues. Due to the existence of isoforms generated by non-enzymatic deaminidation, crystallization of bCyt c is difficult and involves extensive purification and the use of microseeding or the presence of an electric field. Taking advantage of the capacity of cytochrome c (cyt c) to bind anions on its protein surface, the commercially available bCyt c was crystallized without extra purifications, using ammonium sulfate as precipitant and nitrate ions as additives. The structure of the ferric bCyt c in a new crystal form is described and compared with that previously solved at low ionic strength and with those of human and horse cyt c. The overall structure of bCyt c is conserved, while the side chains of several residues that play a role in the interactions of cyt c with its partners have different rotamers in the two structures. The effect of the presence of nitrate ions on the structure of the protein is then evaluated and compared with that observed in the case of ferrous and ferric horse heart cyt c
Metallodrug binding to serum albumin: Lessons from biophysical and structural studies
No full textHuman serum albumin (HSA) plays a major role in the transport of metallodrugs, affecting pharmacokinetics and pharmacodynamics of these molecules. This work highlights the recent achievements in serum albumin metalation by anticancer metallodrugs, with special emphasis on the structure of metallodrug/protein adducts. The effect of protein metalation on HSA structure is discussed together with the possibility to use the metallodrug/HSA adducts as anticancer agents. The structure of HSA, that can be influenced by pH changes and fatty acid binding, is not significantly affected by the metal compound binding. Coordinative bonds and non-covalent interactions can be used by metal compounds to interact with the protein. Several metallodrug binding sites are available on HSA structure: the side chains of Cys34, His105 (subdomain IA), His67 and His247 (i.e. the Site A, the Zn2+ binding site), His128, His146 (subdomain IB), Lys199 and His242 (subdomain IIA), His288 (subdomain IIA), Met298, Met329, His338 (subdomain IIB), Lys436 and His440 (subdomain IIIA), Met548, His535 (subdomain IIIB). Non-covalent metallodrug binding to HSA has been observed in (mainly hydrophobic) pockets lined by residues belonging to the subdomain IB. Pt(II)-based drugs prefer the side chains of His and Met, Ru(II)/(III) compounds the side chains of His (or His and Lys) residues, Au(III)/Au(I)-based drugs prefer the side chain of Cys34, with the Au(III) compounds that can also bind the side chain of His146. This study can assist in the design of new metallodrugs with extended plasma half-life and improved delivery into tumors
Gold metalation of proteins: Structural studies
No full textGold compounds have emerged as a novel class of metallodrugs with a promising future in medicinal inorganic chemistry. Despite gold compounds have been intensively investigated for the treatment of many diseases, their mechanism of action is not fully understood at the molecular level. However, the recognition process by proteins is accepted as a key feature for the biological activity of these molecules. This review presents the research performed during the last decade(s) concerning the structural studies on the products of the reactions between gold-based drugs and proteins. A comparative analysis of the structural features of the known gold/protein adducts suggests that several binding mechanisms are possible. It emerges that gold(III) compounds break down before or upon protein binding and that Au(III) reduces to Au(I) during this process. In agreement with the hard and soft acids and bases (HSAB) theory, Au(I) centers prefer thiolates of free Cys side chains; sulfur atoms of Met are less frequently observed, while N atoms of the side chains of His, Lys, Arg and Gln and O atoms of Glu and Asp are also possible Au binding sites. Au can bridge two protein residue side chains (Cys/Cys, Cys/His, Cys/Asp, Cys/Asn, His/His, His/Lys, His/Gln); Au...π interactions can also be formed. The formation of gold/protein adducts does not alter the overall folding of the investigated proteins, but it can modify the active site conformation, inhibiting the enzymatic activity. The process of gold metalation of proteins is selective
The interaction of rhodium compounds with proteins: A structural overview
No full textRhodium compounds have been used as scaffold for enzyme inhibitors, modulators of protein/protein interactions and of protein aggregation. These compounds have been investigated in their reaction with peptides and proteins with the aim to create artificial metalloenzymes with enhanced catalytic features. Despite several studies have been carried out in this context, the interactions occurring between Rh compounds and these biological molecules and the mechanisms that are responsible for the formation of Rh/peptides and Rh/protein adducts are still largely unknown. This review describes and analyzes the known structures of complexes between protein and Rh compounds and of Rh/protein adducts deposited in the Protein Data Bank. Artificial metalloenzymes are frequently formed by anchoring Rh compounds to proteins via covalent linkage strategies. However, new biohybrids can also be formed by dative anchoring, since coordinative bonds of protein residue side chains with Rh centers (and non-covalent interactions between protein atoms and Rh ligands) can occur. In these adducts, Rh centers preferentially bind the side chains of His, Asp, Asn, Lys and the C-terminal carboxylate. Our analysis provides interesting implications for the design of Rh-based artificial metalloenzymes
Metallodrugs: Mechanisms of Action, Molecular Targets and Biological Activity
No full text: The research interest in the field of inorganic medicinal chemistry had a large increase after the serendipitous discovery of the cytotoxic activity of cisplatin by Rosenberg at the end of 1960s [...]
Exploring the interactions between model proteins and Pd(II) or Pt(II) compounds bearing charged N,N-pyridylbenzimidazole bidentate ligands by X-ray crystallography
No full textPd(ii) and Pt(ii) compounds bearing N,N-pyridylbenzimidazole derivatives with an alkylated sulfonate or phosphonium side chain are able to bind the model protein lysozyme both covalently and non-covalently as an entire compound or as a product of a hydrolysis reaction. The interactions with the protein and the origin of the different behaviors of these complexes were unknown hitherto. Here, we present four crystal structures of their adducts with lysozyme. Pt- and Pd-containing fragments bind the protein with different stoichiometries close to the side chains of His15, Asp87, Asp101 and Asn77. The compounds bearing a phosphonium side chain degrade during the reaction with lysozyme. Data show the origin of the non-covalent mode of binding of Pd and Pt compounds bearing a sulfonate side chain, which drives the recognition process by forming a series of H-bonds and coulombic interactions with positively charged residue side chains. In a separate experiment, the structure of the adduct that is formed when the Pd(ii) compound containing an alkylated sulfonate group reacts with ribonuclease A was also determined. In this structure, the sulfonate-Pd(ii) complex binds the side chain of His105 on the surface of the protein and the side chain of the catalytically important His119 residue. Altogether, our data provide a structural basis for understanding the behavior of the analyzed Pd(ii)- and Pt(ii)-based cisplatin analogues in their reactions with proteins and show the first structural characterization of an adduct comprising a cisplatin analogue that is non-covalently bound to a protein. The results suggest that functionalization of a ligand system with a sulfonate group can significantly alter the protein-binding activity and thus the overall pharmacological profile of Pd(ii)- and Pt(ii)-based drugs
Interaction of Platinum-based Drugs with Proteins: An Overview of Representative Crystallographic Studies
No full textPt-based drugs are widely used in clinics for the treatment of cancer. The mechanism of action of these molecules relies on their interaction with DNA. However, the recognition of these metal compounds by proteins plays an important role in defining pharmacokinetics, side effects and their overall pharmacological profiles. Single crystal X-ray diffraction studies provided important information on the molecular mechanisms at the basis of this process. Here, the molecular structures of representative adducts obtained upon reaction with proteins of selected Pt-based drugs, including cisplatin, carboplatin and oxaliplatin, are briefly described and comparatively examined. Data indicate that metal ligands play a significant role in driving the reaction of Pt compounds with proteins; non-covalent interactions that occur in the early steps of Pt compound/protein recognition process play a crucial role in defining the structure of the final Pt-protein adduct. In the metallated protein structures, Pt centers coordinate few protein side chains, such as His, Met, Cys, Asp, Glu and Lys residues upon releasing labile ligands
Protein Recognition of Gold-Based Drugs: 3D Structure of the Complex Formed When Lysozyme Reacts with Aubipyc
No full textThe structure of the adduct formed in the reaction between Aubipyc,
a cytotoxic organogold(III) compound, and the model protein hen egg white
lysozyme (HEWL) has been solved by X-ray crystallography. It emerges that
Aubipyc, after interaction with HEWL, undergoes reduction of the gold(III) center followed by detaching of the cyclometalated ligand; the resulting naked gold(I) ion is found bound to the protein at Gln121. A direct comparison between the present structure and those previously solved for the lysozyme adducts with other gold(III) compounds demonstrates that coordinated ligands play a key role in the protein−metallodrug recognition process. Structural data support the view that gold(III)-based antitumor prodrugs are activated through metal reduction
Ferritin-based anticancer metallodrug delivery: Crystallographic, analytical and cytotoxicity studies
No full textThe encapsulation of anticancer metal-based drugs within a protein nanocage represents a valuable strategy to improve the efficacy and selectivity of these compounds towards cancer cells. The preparation, characterization of the in vitro cytotoxicity and X-ray structures of several ferritin-metallodrug nanocomposites (mainly containing platinum-, ruthenium- and gold-based anticancer agents) are here reviewed. The molecular mechanisms of action of these Ft-metallodrug adducts are discussed and future directions in the field are outline
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