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Dive into the research topics where Rosa Maria Vitale is active.

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Featured researches published by Rosa Maria Vitale.


Journal of Biological Chemistry | 2007

Insights into the structural basis of the GADD45β-mediated inactivation of the JNK kinase, MKK7/JNKK2

Salvatore Papa; Simona Maria Monti; Rosa Maria Vitale; Concetta Bubici; Shanthi Jayawardena; Kellean Alvarez; Enrico De Smaele; Nina A. Dathan; Carlo Pedone; Menotti Ruvo; Guido Franzoso

NF-κB/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) α-induced killing. With TNFα, NF-κB-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45β, a member of the Gadd45 family, as a pivotal effector of this activity of NF-κB. Inhibition of TNFα-induced JNK signaling by Gadd45β depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45β blunts MKK7, however, is unknown. Here we show that Gadd45β is a structured protein with a predicted four-stranded β-sheet core, five α-helices, and two acidic loops. Association of Gadd45β with MKK7 involves a network of interactions mediated by its putative helices α3 and α4 and loops 1 and 2. Whereas α3 appears to primarily mediate docking to MKK7, loop 1 and α4-loop 2 seemingly afford kinase inactivation by engaging the ATP-binding site and causing conformational changes that impede catalytic function. These data provide a basis for Gadd45β-mediated blockade of MKK7, and ultimately, TNFα-induced PCD. They also have important implications for treatment of widespread diseases.


Journal of Natural Products | 2010

Rare casbane diterpenoids from the Hainan soft coral Sinularia depressa.

Yan Li; Marianna Carbone; Rosa Maria Vitale; Pietro Amodeo; Francesco Castelluccio; Giovanna Sicilia; Ernesto Mollo; Michela Nappo; Guido Cimino; Yue-Wei Guo; Margherita Gavagnin

A series of nine casbane diterpenes, compounds 5-13, exhibiting either cis or trans ring junctions were isolated from the Hainan soft coral Sinularia depressa. The structures of this group of compounds, the basic member of which was named depressin (5), were established by detailed spectroscopic analysis. In addition, the absolute configuration of the main metabolite, 10-hydroxydepressin (7), and of its epimer, 1-epi-10-hydroxydepressin (8), was determined by a combination of conformational analysis and the modified Moshers method. A stereochemical relationship between all isolated molecules was investigated by analyzing their circular dichroism profiles. Antiproliferative and antibacterial activities of the depressins were also evaluated.


Journal of Molecular Biology | 2008

Gadd45β forms a Homodimeric Complex that Binds Tightly to MKK7

Laura Tornatore; Daniela Marasco; Nina A. Dathan; Rosa Maria Vitale; Ettore Benedetti; Salvatore Papa; Guido Franzoso; Menotti Ruvo; Simona Maria Monti

Gadd45 alpha, beta, and gamma proteins, also known as growth arrest and DNA damage-inducible factors, have a number of cellular functions, including cell-cycle regulation and propagation of signals produced by a variety of cellular stimuli, maintaining genomic stability and apoptosis. Furthermore, Gadd45 beta has been indicated as a major player in the endogenous NF-kappaB-mediated resistance to apoptosis in a variety of cell lines. In fibroblasts this mechanism involves the inactivation of MKK7, the upstream activator of JNK, by direct binding within the kinase ATP pocket. On the basis of a number of experimental data, the structures of Gadd45 beta and the Gadd45 beta-MKK7 complex have been predicted recently and data show that interactions are mediated by acidic loops 1 and 2, and helices 3 and 4 of Gadd45 beta. Here, we provide further evidence that Gadd45 beta is a prevailingly alpha-helical protein and that in solution it is able to form non covalent dimers but not higher-order oligomers, in contrast to what has been reported for the homologous Gadd45 alpha. We show that the contact region between the two monomers is comprised of the predicted helix 1 (residues Q17-Q33) and helix 5 (residues K131-R146) of the protein, which appear to be antiparallel and to form a large dimerisation surface not involved in MKK7 recognition. The results suggest the occurrence of a large complex containing at least an MKK7-Gadd45 beta:Gadd45 beta-MKK7 tetrameric unit whose complexity could be further increased by the dimeric nature of the isolated MKK7.


Journal of Medicinal Chemistry | 2008

Carbonic anhydrase inhibitors: bioreductive nitro-containing sulfonamides with selectivity for targeting the tumor associated isoforms IX and XII.

Katia D'Ambrosio; Rosa Maria Vitale; Jean-Michel Dogné; Bernard Masereel; Alessio Innocenti; Andrea Scozzafava; G. De Simone; Claudiu T. Supuran

2-Substituted-5-nitro-benzenesulfonamides incorporating a large variety of secondary/tertiary amines were explored as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), with the aim of designing bioreductive inhibitors targeting the hypoxia overexpressed, tumor-associated isozymes. The compounds were ineffective inhibitors of the cytosolic isoform I, showed a better inhibition of the physiologically relevant CA II (KIs of 8.8-4975 nM), and strongly inhibited the tumor-associated CA IX and XII (KIs of 5.4-653 nM). Some of these compounds showed excellent selectivity ratios for the inhibition of the tumor-associated isozymes over the cytosolic ones (in the range of 10-1395). The X-ray crystal structure of the adduct of hCA II with the lead molecule 2-chloro-5-nitro-benzenesulfonamide as well as molecular modeling studies for interaction with hCA IX afforded a better understanding of factors governing the discrimination of the two isoforms for this type of bioreductive compound targeting specifically hypoxic tumors.


Journal of Molecular Biology | 2009

Structural analysis of BldR from Sulfolobus solfataricus provides insights into the molecular basis of transcriptional activation in archaea by MarR family proteins.

Anna Di Fiore; Gabriella Fiorentino; Rosa Maria Vitale; Raffaele Ronca; Pietro Amodeo; Carlo Pedone; Simonetta Bartolucci; Giuseppina De Simone

The multiple antibiotic resistance regulator (MarR) family constitutes a significant class of transcriptional regulators whose members control a variety of important biological functions such as regulation of response to environmental stress, control of virulence factor production, resistance to antimicrobial agents, and regulation of aromatic catabolic pathways. Although the majority of MarR family members have been characterized as transcriptional repressors, a few examples of transcriptional activators have also been reported. BldR is a newly identified member of this family that has been demonstrated to act as a transcriptional activator in stress response to aromatic compounds in the crenarchaeon Sulfolobus solfataricus. In this work, we report findings on the BldR X-ray crystal structure and present a molecular modeling study on the complex that this protein forms with its cognate DNA sequence, thus providing the first detailed description of the DNA-binding mechanism of an archaeal activator belonging to the MarR family. Two residues responsible for the high binding specificity of this transcriptional regulator were also identified. Our studies demonstrated that, in Archaea, the capability of MarR family members to act as activators or repressors is not related to a particular DNA-binding mechanism but rather could be due to the position of the binding site on the target DNA. Moreover, since genes encoding MarR proteins often control transcription of operons that encode for multisubstrate efflux pumps, our results also provided important insights for the identification of new tools to overcome the microorganisms multidrug resistance.


Bioorganic & Medicinal Chemistry | 2009

A SPR strategy for high-throughput ligand screenings based on synthetic peptides mimicking a selected subdomain of the target protein: A proof of concept on HER2 receptor

Luca Monfregola; Rosa Maria Vitale; Pietro Amodeo; Stefania De Luca

The discovery of pharmaceutical agents is a complex, lengthy and costly process, critically depending on the availability of rapid and efficient screening methods. In particular, when targets are large, multidomain proteins, their complexity may affect unfavorably technical feasibility, costs and unambiguity of binding test interpretation. A possible strategy to overcome these problems relies on molecular design of receptor fragments that are: sensible targets for ligand screenings, conformationally stable also as standalone domains, easily synthesized and immobilized on chip for Biacore experiments. An additional desirable feature for new ligands is the ability of selectively targeting alternative conformational states typical of many proteins. To test the feasibility of such approach on a case with potential applicative interest, we developed a surface plasmon resonance (SPR)-based screening method for drug candidates toward HER2, a Tyr-kinase receptor targeted in anticancer therapies. HER2 was mimicked by HER2-DIVMP, a modified fragment of it immobilized onto the sensor surface specifically modeling HER2 domain IV in its bounded form, designed by structural comparison of HER2 alone and in complex with Herceptin, a monoclonal therapeutic anti-HER2 antibody. This design and its implementation in SPR devices was validated by investigating Herceptin- HER2-DIVMP affinity, measuring its dissociation constant (K(D)=19.2 nM). An efficient synthetic procedure to prepare the HER2-DIVMP peptide was also developed. The HER2-DIVMP conformational stability suggested by experimental and computational results, makes it also a valuable candidate as a mold to design new molecules selectively targeting domain IV of HER2.


Biochemistry | 2008

Structural features of distinctin affecting peptide biological and biochemical properties.

Mauro Dalla Serra; Oscar Cirioni; Rosa Maria Vitale; Giovanni Renzone; Manuela Coraiola; Andrea Giacometti; Cristina Potrich; Elisa Baroni; Graziano Guella; Marina Sanseverino; Stefania De Luca; Giorgio Scalise; Pietro Amodeo; Andrea Scaloni

The antimicrobial peptide distinctin consists of two peptide chains linked by a disulfide bridge; it presents a peculiar fold in water resulting from noncovalent dimerization of two heterodimeric molecules. To investigate the contribution of each peptide chain and the S-S bond to distinctin biochemical properties, different monomeric and homodimeric peptide analogues were synthesized and comparatively evaluated with respect to the native molecule. Our experiments demonstrate that the simultaneous occurrence of both peptide chains and the disulfide bond is essential for the formation of the quaternary structure of distinctin in aqueous media, able to resist protease action. In contrast, distinctin and monomeric and homodimeric analogues exhibited comparable antimicrobial activities, suggesting only a partial contribution of the S-S bond to peptide killing effectiveness. Relative bactericidal properties paralleled liposome permeabilization results, definitively demonstrating that microbial membranes are the main target of distinctin activity. Various biophysical experiments performed in membrane-mimicking media, before and after peptide addition, provided information about peptide secondary structure, lipid bilayer organization, and lipid-peptide orientation with respect to membrane surface. These data were instrumental in the generation of putative models of peptide-lipid supramolecular pore complexes.


Journal of Medicinal Chemistry | 2009

Carbonic anhydrase inhibitors. Comparison of aliphatic sulfamate/bis-sulfamate adducts with isozymes II and IX as a platform for designing tight-binding, more isoform-selective inhibitors

Rosa Maria Vitale; Vincenzo Alterio; Alessio Innocenti; Jean-Yves Winum; Simona Maria Monti; Giuseppina De Simone; Claudiu T. Supuran

Two approaches were used to design inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1): the tail and the ring approaches. Aliphatic sulfamates constitute a class of CA inhibitors (CAIs) that cannot be classified in either one of these categories. We report here the detailed inhibition profile of four such compounds against isoforms CAs I-XIV, the first crystallographic structures of these compounds in adduct with isoform II, and molecular modeling studies for their interaction with hCA IX. Aliphatic monosulfamates/bis-sulfamates were nanomolar inhibitors of hCAs II, IX, and XII, unlike aromatic/heterocyclic sulfonamides that promiscuously inhibit most CA isozymes with low nanomolar affinity. The bis-sulfamates incorporating 8 or 10 carbon atoms showed higher affinity for the tumor-associated hCA IX compared to hCA II, whereas the opposite was true for the monosulfamates. The explanation for their interaction with CA active site furnishes insights for obtaining compounds with increased affinity/selectivity for various isozymes.


Proteins | 2004

Structural features of the inactive and active states of the melanin‐concentrating hormone receptors: Insights from molecular simulations

Rosa Maria Vitale; Carlo Pedone; Pier G. De Benedetti; Francesca Fanelli

Comparative molecular dynamics simulations of both subtypes 1 and 2 of the melanin‐concentrating hormone receptor (MCHR1 and MCHR2, respectively) in their free and hormone‐bound forms have been carried out. The hormone has been used in its full‐length and truncated forms, as well as in 16 mutated forms. Moreover, MCHR1 has been simulated in complex with T‐226296, a novel orally active and selective antagonist. The comparative analysis of an extended number of receptor configurations suggests that the differences between inactive (i.e., free and antagonist‐bound) and active (i.e., agonist‐bound) states of MCHRs involve the receptor portions close to the E/DRY and NPxxY motifs, with prominence to the cytosolic extensions of helices 2, 3, 6, and 7. In fact, the active forms of these receptors share the release of selected intramolecular interactions found in the inactive forms, such as that between R3.50 of the E/DRY motif and D2.40, and that between Y7.53 of the NPxxY motif and F7.60. Another feature of the active forms of both MCHRs is the approach of “helix 8” to the cytosolic extension of helix 3. These features of the active forms are concurrent with the opening of a cleft at the cytosolic end of the helix bundle. For both MCHRs, the agonist‐induced chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor. Proteins 2004.


Journal of Biological Chemistry | 2011

Converting the Highly Amyloidogenic Human Calcitonin into a Powerful Fibril Inhibitor by Three-dimensional Structure Homology with a Non-amyloidogenic Analogue

Giuseppina Andreotti; Rosa Maria Vitale; Carmit Avidan-Shpalter; Pietro Amodeo; Ehud Gazit; Andrea Motta

Irreversible aggregation limits bioavailability and therapeutic activity of protein-based drugs. Here we show that an aggregation-resistant mutant can be engineered by structural homology with a non-amyloidogenic analogue and that the aggregation-resistant variant may act as an inhibitor. This strategy has successfully been applied to the amyloidogenic human calcitonin (hCT). Including only five residues from the non-amyloidogenic salmon calcitonin (sCT), we obtained a variant, polar human calcitonin (phCT), whose solution structure was shown by CD, NMR, and calculations to be practically identical to that of sCT. phCT was also observed to be a potent amyloidogenesis inhibitor of hCT when mixed with it in a 1:1 ratio. Fibrillation studies of phCT and the phCT-hCT mixture mimicked the sCT behavior in the kinetics and shapes of the fibrils with a dramatic reduction with respect to hCT. Finally, the effect of phCT alone and of the mixture on the intracellular cAMP level in T47D cells confirmed for the mutant and the mixture their calcitonin-like activity, exhibiting stimulation effects identical to those of sCT, the current therapeutic form. The strategy followed appears to be suitable to develop new forms of hCT with a striking reduction of aggregation and improved activity. Finally, the inhibitory properties of the aggregation-resistant analogue, if confirmed for other amyloidogenic peptides, may favor a new strategy for controlling fibril formation in a variety of human diseases.

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Pietro Amodeo

National Research Council

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Carlo Pedone

University of Naples Federico II

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Ettore Benedetti

University of Naples Federico II

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Andrea Scaloni

National Research Council

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Michele Saviano

University of Naples Federico II

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Giuseppina De Simone

University of Naples Federico II

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