17 research outputs found
Cisplatin Binding to Proteins: Molecular Structure of the Ribonuclease A Adduct
The crystal structure of the main
adduct formed in the reaction between cisplatin and bovine pancreatic
ribonuclease is reported here. Notably, in both of the protein molecules
present in the asymmetric unit, platinumÂ(II) binding takes place exclusively
at the level of Met29. In one of the two molecules, the Gln28 side
chain completes the platinum coordination sphere, anchoring the cisplatin
fragment to the protein in a bidentate fashion. These results contain
interesting implications for understanding the biological chemistry
of this important drug
Protein Recognition of Gold-Based Drugs: 3D Structure of the Complex Formed When Lysozyme Reacts with Aubipy<sup>c</sup>
The
structure of the adduct formed in the reaction between Aubipy<sup>c</sup>, a cytotoxic organogoldÂ(III) compound, and the model protein
hen egg white lysozyme (HEWL) has been solved by X-ray crystallography.
It emerges that Aubipy<sup>c</sup>, after interaction with HEWL, undergoes
reduction of the goldÂ(III) center followed by detaching of the cyclometalated
ligand; the resulting naked goldÂ(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 goldÂ(III) compounds
demonstrates that coordinated ligands play a key role in the proteinâmetallodrug
recognition process. Structural data support the view that goldÂ(III)-based
antitumor prodrugs are activated through metal reduction
Multiple and Variable Binding of Pharmacologically Active Bis(maltolato)oxidovanadium(IV) to Lysozyme
The interaction with
proteins of metal-based drugs plays a crucial
role in their transport, mechanism, and activity. For an active MLn complex, where L is the organic carrier,
various binding modes (covalent and non-covalent, single or multiple)
may occur and several metal moieties (M, ML, ML2, etc.)
may interact with proteins. In this study, we have evaluated the interaction
of [VIVOÂ(malt)2] (bisÂ(maltolato)ÂoxidovanadiumÂ(IV)
or BMOV, where malt = maltolato, i.e., the common name for 3-hydroxy-2-methyl-4H-pyran-4-onato) with the model protein hen egg white lysozyme
(HEWL) by electrospray ionization mass spectrometry, electron paramagnetic
resonance, and X-ray crystallography. The multiple binding of different
V-containing isomers and enantiomers to different sites of HEWL is
observed. The data indicate both non-covalent binding of cis-[VOÂ(malt)2(H2O)] and [VOÂ(malt)Â(H2O)3]+ and covalent binding of [VOÂ(H2O)3â4]2+ and cis-[VOÂ(malt)2] and other V-containing fragments to the side chains of Glu35,
Asp48, Asn65, Asp87, and Asp119 and to the C-terminal carboxylate.
Our results suggest that the multiple and variable interactions of
potential VIVOL2 drugs with proteins can help
to better understand their solution chemistry and contribute to define
the molecular basis of the mechanism of action of these intriguing
molecules
Investigating the Ruthenium Metalation of Proteins: Xâray Structure and Raman Microspectroscopy of the Complex between RNase A and AziRu
A Raman-assisted
crystallographic study on the adduct between AziRu, a RuÂ(III) complex
with high antiproliferative activity, and RNase A is presented. The
protein structure is not perturbed significantly by the Ru label.
The metal coordinates to ND atoms of His105 or of His119 imidazole
rings, losing all of its original ligands but retaining octahedral,
although distorted, coordination geometry. The AziRu binding inactivates
the enzyme, suggesting that its antitumor action can be exerted by
a mechanism of competitive inhibition
Effect of Equatorial Ligand Substitution on the Reactivity with Proteins of Paddlewheel Diruthenium Complexes: Structural Studies
The paddlewheel [Ru2Cl(O2CCH3)4] complex was previously reported to react with
the model
protein hen egg white lysozyme (HEWL), forming adducts with two diruthenium
moieties bound to Asp101 and Asp119 side chains upon the release of
one acetate. To study the effect of the equatorial ligands on the
reactivity with proteins of diruthenium compounds, X-ray structures
of the adducts formed when HEWL reacts with [Ru2Cl(D-p-FPhF)(O2CCH3)3] [D-p-FPhF = N,NâČ-bis(4-fluorophenyl)formamidinate]
under different conditions were solved. [Ru2Cl(D-p-FPhF)(O2CCH3)3] is bonded
through their equatorial positions to the Asp side chains. Protein
binding occurs cis or trans to D-p-FPhF. Lys or Arg
side chains or even main-chain carbonyl groups can coordinate to the
diruthenium core at the axial site. Data help to understand the reactivity
of paddlewheel diruthenium complexes with proteins, providing useful
information for the design of new artificial diruthenium-containing
metalloenzymes with potential applications in the fields of catalysis,
biomedicine, and biotechnology
Interaction of Anticancer Ruthenium Compounds with Proteins: High-Resolution Xâray Structures and Raman Microscopy Studies of the Adduct between Hen Egg White Lysozyme and AziRu
The
binding properties of AziRu, a rutheniumÂ(III) complex with high antiproliferative
activity, toward a hen egg white lysozyme have been investigated by
X-ray crystallography and Raman microscopy. The data provide clear
evidence on the mechanism of AziRuâprotein adduct formation
and of ligand exchange in the crystal state
Peculiar Features in the Crystal Structure of the Adduct Formed between <i>cis</i>-PtI<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub> and Hen Egg White Lysozyme
The reactivity of <i>cis</i>-diamminediiodidoplatinumÂ(II), <i>cis</i>-PtI<sub>2</sub>(NH<sub>3</sub>)<sub>2</sub>, the iodo analogue of cisplatin, with
hen egg white lysozyme (HEWL) was investigated by electrospray ionization
mass spectrometry and X-ray crystallography. Interestingly, the study
compound forms a stable 1:1 protein adduct for which the crystal structure
was solved at 1.99 Ă
resolution. In this adduct, the Pt<sup>II</sup> center, upon release of one ammonia ligand, selectively coordinates
to the imidazole of His15. Both iodide ligands remain bound to platinum,
with this being a highly peculiar and unexpected feature. Notably,
two equivalent modes of Pt<sup>II</sup> binding are possible that
differ only in the location of I atoms with respect to ND1 of His15.
The structure of the adduct was compared with that of HEWLâcisplatin,
previously described; differences are stressed and their important
mechanistic implications discussed
Interaction between Proteins and Ir Based CO Releasing Molecules: Mechanism of Adduct Formation and CO Release
Carbon
monoxide releasing molecules (CORMs) have important bactericidal,
anti-inflammatory, neuroprotective, and antiapoptotic effects and
can be used as tools for CO physiology experiments, including studies
on vasodilation. In this context, a new class of CO releasing molecules,
based on pentachlorocarbonyliridateÂ(III) derivative have been recently
reported. Although there is a growing interest in the characterization
of proteinâCORMs interactions, only limited structural information
on CORM binding to protein and CO release has been available to date.
Here, we report six different crystal structures describing events
ranging from CORM entrance into the protein crystal up to the CO release
and a biophysical characterization by isothermal titration calorimetry,
Raman microspectroscopy, and molecular dynamics simulations of the
complex between a pentachlorocarbonyliridateÂ(III) derivative and hen
egg white lysozyme, a model protein. Altogether, the data indicate
the formation of a complex in which the ligand can bind to different
sites of the protein surface and provide clues on the mechanism of
adduct formation and CO release
Interactions between Anticancer <i>trans</i>-Platinum Compounds and Proteins: Crystal Structures and ESI-MS Spectra of Two Protein Adducts of <i>trans</i>-(Dimethylamino)(methylamino)dichloridoplatinum(II)
The adducts formed between <i>trans</i>-(dimethylamino)Â(methylamino)ÂdichloridoplatinumÂ(II),
[t-PtCl<sub>2</sub>(dma)Â(ma)], and two model proteins, i.e., hen egg
white lysozyme and bovine pancreatic ribonuclease, were independently
characterized by X-ray crystallography and electrospray ionization
mass spectrometry. In these adducts, the Pt<sup>II</sup> center, upon
chloride release, coordinates either to histidine or aspartic acid
residues while both alkylamino ligands remain bound to the metal.
Comparison with the cisplatin derivatives of the same proteins highlights
for [t-PtCl<sub>2</sub>(dma)Â(ma)] a kind of biomolecular metalation
remarkably different from that of cisplatin
α-Thalassemia Associated with Hb Instability: A Tale of Two Features. The Case of Hb Rogliano or α1 Cod 108(G15)ThrâAsn and Hb Policoro or α2 Cod 124(H7)SerâPro.
<div><p>We identified two new variants in the third exon of the α-globin gene in families from southern Italy: the Hb Rogliano, α1 cod108 ACC>AAC or α1[α108(G15)ThrâAsn] and the Hb Policoro, α2 cod124 TCC>CCC or α2[α124(H7)SerâPro]. The carriers showed mild α-thalassemia phenotype and abnormal hemoglobin stability features. These mutations occurred in the G and H helices of the α-globin both involved in the specific recognition of AHSP and ÎČ1 chain. Molecular characterization of mRNA, globin chain analyses and molecular modelling studies were carried out to highlight the mechanisms causing the α-thalassemia phenotype. The results demonstrated that the α-thalassemia defect associated with the two Hb variants originated by different defects. Hb Rogliano showed an intrinsic instability of the tetramer due to anomalous intra- and inter-chain interactions suggesting that the variant chain is normally synthesized and complexed with AHSP but rapidly degraded because it is unable to form the α1ÎČ1 dimers. On the contrary in the case of Hb Policoro two different molecular mechanisms were shown: the reduction of the variant mRNA level by an unclear mechanism and the protein instability due to impairment of AHSP interaction. These data highlighted that multiple approaches, including mRNA quantification, are needed to properly identify the mechanisms leading to the α-thalassemia defect. Elucidation of the specific mechanism leads to the definition of a given phenotype providing important guidance for the diagnosis of unstable variants.</p></div