S Fermandjian

Ecole normale supérieure de Cachan, Cachon, Île-de-France, France

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Publications (101)379.75 Total impact

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    ABSTRACT: Aim HIV integrase (IN) is a privileged target for antiviral treatments. These induce the emergence of resistant strains, prompting the search of new drugs. To better understand the relationships between structure and function of IN and identify new anti-HIV inhibitors we prepared antibodies recognizing the IN a4 helix that binds viral DNA ends and contributes to the integration process and antibodies recognizing a loop in between the a4 and a5 helices which participates to the binding of LEDGF a protein that helps IN to anchor viral DNA. Materials and methods Polypeptide K159 (sequence 147-175 of IN) was injected to mice. Several hybridomas producing monoclonal anti-bodies (Mabs) were obtained Mabs were characterized by ELISA and blotting techniques using peptide fragments, IN and viral DNA sequences. Results We prepared two Mabs (Mab-a4 and Mab-loop) exhibit-ing high affinities against the antigenic peptide K159 and IN. An epitope mapping showed that Mab-a4 interacted with N-terminal segment (147-163) and Mab-loop with the C-terminal (164-175). Mab-a4 blocked the interac-tion of IN with viral DNA end, while the loop segment 164-175 recognized by the Mab-loop constitutes a strong epitope also found in African seropositive patients. Spec-troscopic studies of the antibody-antigen complexes are under progress. Crystallization of the Fab moiety of Mab-a4 has been recently obtained.
    Retrovirology 05/2012; · 5.66 Impact Factor
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    ABSTRACT: Integration of HIV DNA into host chromosome requires a 3'-processing (3'-P) and a strand transfer (ST) reactions catalyzed by virus integrase (IN). Raltegravir (RAL), commonly used in AIDS therapy, belongs to the family of IN ST inhibitors (INSTIs) acting on IN-viral DNA complexes (intasomes). However, studies show that RAL fails to bind IN alone, but nothing has been reported on the behaviour of RAL toward free viral DNA. Here, we assessed whether free viral DNA could be a primary target for RAL, assuming that the DNA molecule is a receptor for a huge number of pharmacological agents. Optical spectroscopy, molecular dynamics and free energy calculations, showed that RAL is a tight binder of both processed and unprocessed LTR (long terminal repeat) ends. Complex formation involved mainly van der Waals forces and was enthalpy driven. Dissociation constants (Kds) revealed that RAL affinity for unbound LTRs was stronger than for bound LTRs. Moreover, Kd value for binding of RAL to LTRs and IC50 value (half concentration for inhibition) were in same range, suggesting that RAL binding to DNA and ST inhibition are correlated events. Accommodation of RAL into terminal base-pairs of unprocessed LTR is facilitated by an extensive end fraying that lowers the RAL binding energy barrier. The RAL binding entails a weak damping of fraying and correlatively of 3'-P inhibition. Noteworthy, present calculated RAL structures bound to free viral DNA resemble those found in RAL-intasome crystals, especially concerning the contacts between the fluorobenzyl group and the conserved 5'C(4)pA(3)3' step. We propose that RAL inhibits IN, in binding first unprocessed DNA. Similarly to anticancer drug poisons acting on topoisomerases, its interaction with DNA does not alter the cut, but blocks the subsequent joining reaction. We also speculate that INSTIs having viral DNA rather IN as main target could induce less resistance.
    PLoS ONE 01/2012; 7(7):e40223. · 3.53 Impact Factor
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    ABSTRACT: Monoclonal antibodies (MAbas) constitute remarkable tools to analyze the relationship between the structure and the function of a protein. By immunizing a mouse with a 29mer peptide (K159) formed by residues 147 to 175 of the HIV-1 integrase (IN), we obtained a monoclonal antibody (MAba4) recognizing an epitope lying in the N-terminal portion of K159 (residues 147-166 of IN). The boundaries of the epitope were determined in ELISA assays using peptide truncation and amino acid substitutions. The epitope in K159 or as a free peptide (pep-a4) was mostly a random coil in solution, while in the CCD (catalytic core domain) crystal, the homologous segment displayed an amphipathic helix structure (α4-helix) at the protein surface. Despite this conformational difference, a strong antigenic crossreactivity was observed between pep-a4 and the protein segment, as well as K156, a stabilized analogue of pep-a4 constrained into helix by seven helicogenic mutations, most of them involving hydrophobic residues. We concluded that the epitope is freely accessible to the antibody inside the protein and that its recognition by the antibody is not influenced by the conformation of its backbone and the chemistry of amino acids submitted to helicogenic mutations. In contrast, the AA →Glu mutations of the hydrophilic residues Gln148, Lys156 and Lys159, known for their interactions with LTRs (long terminal repeats) and inhibitors (5CITEP, for instance), significantly impaired the binding of K156 to the antibody. Moreover, we found that in competition ELISAs, the processed and unprocessed LTR oligonucleotides interfered with the binding of MAba4 to IN and K156, confirming that the IN α4-helix uses common residues to interact with the DNA target and the MAba4 antibody. This also explains why, in our standard in vitro concerted integration assays, MAba4 strongly impaired the IN enzymatic activity.
    PLoS ONE 01/2010; 5(12):e16001. · 3.53 Impact Factor
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    ABSTRACT: Amplification of chirality has been reported in polymeric systems. It has also been shown that related effects can occur in polymer-like dynamic supramolecular aggregates, if a subtle balance between noncovalent interactions allows the coupling between a chiral information and a cooperative aggregation process. In this context, we report a strong majority-rules effect in the formation of chiral dynamic nanotubes from chiral bisurea monomers. Furthermore, similar helical nanotubes (with the same circular dichroism signature) can be obtained from racemic monomers in a chiral solvent. Competition experiments reveal the relative strength of the helical bias induced by the chiral monomer or by the chiral solvent. The nanotube handedness is imposed by the monomer chirality, whatever the solvent chirality. However, the chirality of the solvent has a significant effect on the degree of chiral induction.
    Chemistry 11/2009; 16(1):173-7. · 5.93 Impact Factor
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    ABSTRACT: HIV-1 integrase (IN) catalyzes integration of viral DNA into cell DNA through 3'-processing of viral DNA and strand transfer reactions. To learn on binding of IN to DNAs and IN inhibition we applied spectroscopy (circular dichroism, fluorescence) in a simplified model consisting in a peptide analogue (K156) of alpha4 helix involved in recognition of viral and cell DNA; an oligonucleotide corresponding to the U5' LTR DNA end; and an inhibitor (TB11) of the diketo acid (DKA) family. Results extrapolated to IN show that: the enzyme binds viral DNA with high affinity and specificity, but cell DNA with low affinity and specificity; the affinity of TB11 for IN is high enough to impair the binding of IN to cell DNA, but not to viral DNA. This explains why TB11 is an inhibitor of strand transfer but not of 3'-processing. These results can help in the search of new IN inhibitors.
    Neurochemical Research 11/2009; 35(6):888-93. · 2.13 Impact Factor
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    ABSTRACT: HIV-1 integrase integrates retroviral DNA through 3'-processing and strand transfer reactions in the presence of a divalent cation (Mg(2+) or Mn(2+)). The alpha4 helix exposed at the catalytic core surface is essential to the specific recognition of viral DNA. To define group determinants of recognition, we used a model composed of a peptide analogue of the alpha4 helix, oligonucleotides mimicking processed and unprocessed U5 LTR end and 5 mM Mg(2+). Circular dichroism, fluorescence and NMR experiments confirmed the implication of the alpha4 helix polar/charged face in specific and non-specific bindings to LTR ends. The specific binding requires unprocessed LTR ends-i.e. an unaltered 3'-processing site CA downward arrowGT3'-and is reinforced by Mg(2+) (K(d) decreases from 2 to 0.8 nM). The latter likely interacts with the ApG and GpT3' steps of the 3'-processing site. With deletion of GT3', only persists non-specific binding (K(d) of 100 microM). Proton chemical shift deviations showed that specific binding need conserved amino acids in the alpha4 helix and conserved nucleotide bases and backbone groups at LTR ends. We suggest a conserved recognition mechanism based on both direct and indirect readout and which is subject to evolutionary pressure.
    Nucleic Acids Research 10/2009; 37(22):7691-700. · 8.81 Impact Factor
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    ABSTRACT: Integrase (IN) of the type 1 human immunodeficiency virus (HIV-1) catalyzes the integration of viral DNA into host cellular DNA. We identified a bi-helix motif (residues 149-186) in the crystal structure of the catalytic core (CC) of the IN-Phe185Lys variant that consists of the alpha(4) and alpha(5) helices connected by a 3 to 5-residue turn. The motif is embedded in a large array of interactions that stabilize the monomer and the dimer. We describe the conformational and binding properties of the corresponding synthetic peptide. This displays features of the protein motif structure thanks to the mutual intramolecular interactions of the alpha(4) and alpha(5) helices that maintain the fold. The main properties are the binding to: 1- the processing-attachment site at the LTR (long terminal repeat) ends of virus DNA with a K(d) (dissociation constant) in the sub-micromolar range; 2- the whole IN enzyme; and 3- the IN binding domain (IBD) but not the IBD-Asp366Asn variant of LEDGF (lens epidermal derived growth factor) lacking the essential Asp366 residue. In our motif, in contrast to the conventional HTH (helix-turn-helix), it is the N terminal helix (alpha(4)) which has the role of DNA recognition helix, while the C terminal helix (alpha(5)) would rather contribute to the motif stabilization by interactions with the alpha(4) helix. The motif, termed HTHi (i, for inverted) emerges as a central piece of the IN structure and function. It could therefore represent an attractive target in the search for inhibitors working at the DNA-IN, IN-IN and IN-LEDGF interfaces.
    PLoS ONE 02/2009; 4(1):e4081. · 3.53 Impact Factor
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    ABSTRACT: Topoisomerase II enzymes are essential enzymes that modulate DNA topology and play a role in chromatin compaction. While these enzymes appear to recognize and cleave the DNA in a nonrandom fashion, factors that underlie enzyme specificity remain an enigma. To gain new insights on these topics, we undertake, using NMR and molecular dynamics methods, studies of the structural and dynamic features of a 21 bp DNA segment preferentially cleaved by topoisomerases II. The large size of the oligonucleotide did not hamper the determination of structures of sufficient quality, and numerous interesting correlations between helicoidal parameters already depicted in crystals and molecular dynamics simulations are recovered here. The main feature of the sequence is the occurrence of a large opening of the base pairs in a four-residue AT-rich region located immediately at the 5′ end of one of the cleaved sites. This opening seems to be largely dependent on sequence context, since a similar opening is not found in the other AT base pairs of the sequence. Furthermore, two adenine nucleotides of the same portion of the oligonucleotide present slow internal motions at the NMR timescale, revealing particular base dynamics. In conclusion, this AT-rich region presents the most salient character in the sequence and could be involved in the preferential cleavage by topoisomerase II. The examination of preferred sites in the literature pointed out the frequent occurrence of AT-rich sequences, namely matrix attachment region and scaffold attachment region sequences, at the sites cleaved by topoisomerase II. We could infer that the particular flexibility of these sequences plays an important role in enabling the formation of a competent cleavage complex. The sequences could then be selected based on their facility to undertake conformational change during the complex formation, rather than purely based on binding affinity.
    Journal of Molecular Biology. 09/2008;
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    ABSTRACT: Topoisomerase II enzymes are essential enzymes that modulate DNA topology and play a role in chromatin compaction. While these enzymes appear to recognize and cleave the DNA in a nonrandom fashion, factors that underlie enzyme specificity remain an enigma. To gain new insights on these topics, we undertake, using NMR and molecular dynamics methods, studies of the structural and dynamic features of a 21 bp DNA segment preferentially cleaved by topoisomerases II. The large size of the oligonucleotide did not hamper the determination of structures of sufficient quality, and numerous interesting correlations between helicoidal parameters already depicted in crystals and molecular dynamics simulations are recovered here. The main feature of the sequence is the occurrence of a large opening of the base pairs in a four-residue AT-rich region located immediately at the 5' end of one of the cleaved sites. This opening seems to be largely dependent on sequence context, since a similar opening is not found in the other AT base pairs of the sequence. Furthermore, two adenine nucleotides of the same portion of the oligonucleotide present slow internal motions at the NMR timescale, revealing particular base dynamics. In conclusion, this AT-rich region presents the most salient character in the sequence and could be involved in the preferential cleavage by topoisomerase II. The examination of preferred sites in the literature pointed out the frequent occurrence of AT-rich sequences, namely matrix attachment region and scaffold attachment region sequences, at the sites cleaved by topoisomerase II. We could infer that the particular flexibility of these sequences plays an important role in enabling the formation of a competent cleavage complex. The sequences could then be selected based on their facility to undertake conformational change during the complex formation, rather than purely based on binding affinity.
    Journal of Molecular Biology 07/2008; 381(3):692-706. · 3.91 Impact Factor
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    ABSTRACT: By binding to the CArG box sequence, the serum response factor (SRF) activates several muscle-specific genes, as well as genes that respond to mitogens. The core domain of the SRF (core-SRF) binds as a dimer to the CArG box C-5C-4A-3T-2A-1T+1T+2A+3G+4G+5 of the c-fos serum response element (SREfos). However, previous studies using 20-mer DNAs have shown that the binding stoichiometry of core-SRF is significantly altered by mutations C-5-->G (SREGfos) and C-5C-4-->GG (SREGGfos) of the CArG box [A Huet, A Parlakian, M-C Arnaud, J-M Glandières, P Valat, S Fermandjian, D Paulin, B Alpert & C Zentz (2005) FEBS J272, 3105-3119]. To understand these effects, we carried out a comparative analysis of the three 20-mer DNAs SREfos, SREGfos and SREGGfos in aqueous solution. Their CD spectra were of the B-DNA type with small differences generated by variations in the mutual arrangement of the base pairs. Analysis by singular value decomposition of a set of Raman spectra recorded as a function of temperature, revealed a premelting transition associated with a conformational shift in the DNA double helices from a bent to a linear form. Time-resolved fluorescence anisotropy shows that the fluorescein reporter linked to the oligonucleotide 5'-ends experiences twisting motions of the double helices related to the interconversion between bent and linear conformers. The three SREs present various bent populations submitted, however, to particular internal dynamics, decisive for the mutual adjustment of binding partners and therefore specific complex formation.
    FEBS Journal 05/2007; 274(9):2333-48. · 4.25 Impact Factor
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    ABSTRACT: The dynamics of the DNA phosphodiester backbone conformations have been studied for a strong topoisomerase II cleavage site (site 22) using molecular dynamics simulations in explicit water and in the presence of sodium ions. We investigated the backbone motions and more particularly the BI/BII transitions involving the epsilon and zeta angles. The consensus cleavage site is adjacent to the phosphate which shows the most important phosphodiester backbone flexibility in the sequence. We infer that these latter properties could be responsible for the preferential cleavage at this site possibly through the perturbation of the cleavage/ligation activities of the topoisomerase II. More generally, the steps pur-pur and pyr-pur are those presenting the highest BII contents. Relations are observed between the backbone phosphodiester BI/BII transitions and the flexibility of the deoxyribose sugar and the helical parameters such as roll. The roll is sequence dependent when the related phosphate is in the BI form, whereas this appears not to be true when it is in the BII form. The BI/BII transitions are associated with water migration, and new relations are observed with counterions. Indeed, it is observed that a strong coupling exists between the BII form and the presence of sodium ions near the adjacent sugar deoxyribose. The presence of sodium ions in the O4' surroundings or their binding could assist the BI to BII transition by furnishing energy. The implications of these new findings and, namely, their importance in the context of the sequence-dependent behavior of BI/BII transitions will be investigated in future studies.
    The Journal of Physical Chemistry B 04/2007; 111(16):4235-43. · 3.61 Impact Factor
  • Brigitte René, Serge Fermandjian, Olivier Mauffret
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    ABSTRACT: DNA topoisomerase II is an enzyme that specializes in DNA disentanglement. It catalyzes the interconversion of DNA between different topological states. This event requires the passage of one duplex through another one via a transient double-strand break. Topoisomerase II is able to process any type of DNA, including structures such as DNA juxtapositions (crossovers), DNA hairpins or cruciforms, which are recognized with high specificity. In this review, we focused our attention on topoisomerase II recognizing DNA substrates that possess particular geometries. A strong cleavage site, as we identified in pBR322 DNA in the presence of ellipticine (site 22), appears to be characterized by a cruciform structure formed from two stable hairpins. The same sequence could also constitute a four-way junction structure stabilized by interactions involving ATC sequences. The latter have been shown to be able to promote Holliday junctions. We reviewed the recent literature that deals with the preferential recognition of crossovers by various topoisomerases. The single molecule relaxation experiments have demonstrated the differential abilities of the topoisomerases to recognize crossovers. It appears that enzymes, which distinguish the chirality of the crossovers, possess specialized domains dedicated to this function. We also stress that the formation of crossovers is dependent on the presence of adequate stabilizing sequences. Investigation of the impact of such structures on enzyme activity is important in order to both improve our knowledge of the mechanism of action of the topoisomerase II and to develop new inhibitors of this enzyme.
    Biochimie. 04/2007;
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    ABSTRACT: Candida guilliermondii and human DNA topoisomerases I are inhibited by PL (pyridoxal), PLP (pyridoxal 5'-phosphate) and PLP-AMP (pyridoxal 5'-diphospho-5'-adenosine) (PL<PLP<PLP-AMP). We have recently shown that PLP acted as a competitive inhibitor of C. guilliermondii topoisomerase I, impeding the formation of the cleavable complex from a selective binding to an active site lysine. The targeted lysine in C. guilliermondii topoisomerase I occupies a position equivalent to that of lysine 532 (K(532)) in human topoisomerase I. K(532) acts as a general acid catalyst and is essential for the enzyme activity. This observation has suggested that, in the cell, PLP could down-regulate topoisomerases IB. We have proposed that PLP could be used as a new lead for anticancer drugs trapping the active site lysine (K(532)) and also as a tool to explore the enzyme dynamics required for catalysis. Now we explore the effects of PL, PLP and PLP-AMP on topoisomerases by a molecular modelling approach using the crystal structure of the human topoisomerase I active site and the conformation of K(39)-PLP moiety in Bacillus subtilis alanine racemase as templates. In the modified topoisomerase I several reactive atoms of the K(532)-PLP moiety are at close distance of the catalytic residues R(488), R(590), H(632) and Y(723,) suggesting that PLP develops disturbing interactions with these important residues. These interactions and the corresponding induced fit in the active site conformation are compared with the ones occurring with PL and PLP-AMP. The results could be useful in the search of topoisomerase I inhibitors related to the pyridoxal family.
    Biochimie 04/2007; 89(4):468-73. · 3.14 Impact Factor
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    Brigitte René, Serge Fermandjian, Olivier Mauffret
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    ABSTRACT: DNA topoisomerase II is an enzyme that specializes in DNA disentanglement. It catalyzes the interconversion of DNA between different topological states. This event requires the passage of one duplex through another one via a transient double-strand break. Topoisomerase II is able to process any type of DNA, including structures such as DNA juxtapositions (crossovers), DNA hairpins or cruciforms, which are recognized with high specificity. In this review, we focused our attention on topoisomerase II recognizing DNA substrates that possess particular geometries. A strong cleavage site, as we identified in pBR322 DNA in the presence of ellipticine (site 22), appears to be characterized by a cruciform structure formed from two stable hairpins. The same sequence could also constitute a four-way junction structure stabilized by interactions involving ATC sequences. The latter have been shown to be able to promote Holliday junctions. We reviewed the recent literature that deals with the preferential recognition of crossovers by various topoisomerases. The single molecule relaxation experiments have demonstrated the differential abilities of the topoisomerases to recognize crossovers. It appears that enzymes, which distinguish the chirality of the crossovers, possess specialized domains dedicated to this function. We also stress that the formation of crossovers is dependent on the presence of adequate stabilizing sequences. Investigation of the impact of such structures on enzyme activity is important in order to both improve our knowledge of the mechanism of action of the topoisomerase II and to develop new inhibitors of this enzyme.
    Biochimie 04/2007; 89(4):508-15. · 3.14 Impact Factor
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    ABSTRACT: (13)C, (15)N labeling of biomolecules allows easier assignments of NMR resonances and provides a larger number of NMR parameters, which greatly improves the quality of DNA structures. However, there is no general DNA-labeling procedure, like those employed for proteins and RNAs. Here, we describe a general and widely applicable approach designed for preparation of isotopically labeled DNA fragments that can be used for NMR studies. The procedure is based on the PCR amplification of oligonucleotides in the presence of labeled deoxynucleotides triphosphates. It allows great flexibility thanks to insertion of a short DNA sequence (linker) between two repeats of DNA sequence to study. Size and sequence of the linker are designed as to create restriction sites at the junctions with DNA of interest. DNA duplex with desired sequence and size is released upon enzymatic digestion of the PCR product. The suitability of the procedure is validated through the preparation of two biological relevant DNA fragments.
    Journal of Biomolecular NMR 12/2006; 36(3):137-46. · 2.85 Impact Factor
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    ABSTRACT: We rank the reactivity of the adenyl residues (A) of model DNA and RNA molecules with electropositive subnano size [Ag]n+ sites as a function of nucleic acid primary sequences and secondary structures and in the presence of biological amounts of Cl- and Na+ or Mg2+ ions. In these conditions A is markedly more reactive than any other nucleic acid bases. A reactivity is higher in ribo (r) than in deoxyribo (d) species [pA>pdA and (pA)n>(pdA)n]. Base pairing decreases A reactivity in corresponding duplexes but much less in r than in d. In linear single and paired dCAG or dGAC loci, base stacking inhibits A reactivity even if A is bulged or mispaired (A.A). dA tracts are highly reactive only when dilution prevents self-association and duplex structures. In d hairpins the solvent-exposed A residues are reactive in CAG and GAC triloops and even more in ATC loops. Among the eight rG1N2R3A4 loops, those bearing a single A (A4) are the least reactive. The solvent-exposed A2 is reactive, but synergistic structural transitions make the initially stacked A residues of any rGNAA loop much more reactive. Mg2+ cross-bridging single strands via phosphates may screen A reactivity. In contrast d duplexes cross-bridging enables "A flipping" much more in rA.U pairs than in dA.T. Mg2+ promotes A reactivity in unpaired strands. For hairpins Mg2+ binding stabilizes the stems, but according to A position in the loops, A reactivity may be abolished, reduced, or enhanced. It is emphasized that not only accessibility but also local flexibility, concerted docking, and cation and anion binding control A reactivity.
    Biopolymers 06/2006; 82(1):6-28. · 2.88 Impact Factor
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    ABSTRACT: The eukaryotic topoisomerase II is an ubiquitous nuclear enzyme involved in vital cellular functions. It is also the target for some of the most active anticancer drugs. In the various crystal structures of yeast topoisomerase II, the 701–748 segment homologous to the human topoisomerase II α 724–771 segment folds into a compact α2β1α3tα4 conformation, hereafter termed α2HTH module (helix turn helix (HTH), α3tα4). The crystal structure of gyrase A has suggested a model wherein HTH is involved in both the enzyme dimerization and the binding to DNA. These two properties were investigated in solution, using the recombinant α2HTH module of human topoisomerase II α and its synthetic components HTH, α4, α3 and turn. The homology-based structure model of human α2HTH superposed that of yeast in the crystal structure with a rmsd of 1.03 Å. Circular dichroism spectra showed that the helical content of human α2HTH in solution is similar to that of its counterpart within yeast topoisomerase II in the solid state. The chemical cross-linking data indicated that α2HTH self-associated into dimers while gel mobility shift assays and anisotropy fluorescence titrations demonstrated that α2HTH, HTH and α4, but not α3, bind efficiently to DNA (dissociation constants of 3.10–7 M for α2HTH and α4, of 3.10–6 M for HTH and of only 1.10–5 M for α3). Correlatively, α2HTH, α4 and HTH, but not α3, were able to inhibit topoisomerase II in DNA relaxation assays, stipulating that α4 is the DNA recognition helix. All suggests that the α2HTH module once separated from the whole protein conserves a compact conformation, integral to specific dimerization and DNA recognition. The module may thus be used for the search of drugs efficient in hindering topoisomerase II dimerization or binding to DNA.
    Biochimie 01/2006; 88(3):253-263. · 3.14 Impact Factor
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    Biochimie 01/2006; 88(3-4):253-263. · 3.14 Impact Factor
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    ABSTRACT: Three synthetic oligopeptides (EAA26, K156 and E156) mutant of the a-4 helix of the HIV-1 integrase and having, respectively, 26, 24 and 24 aminoacids showed variable oligomerisation trend as detected by the ESI-MS (electrospray mass spectrometry) or CD (circular dichroism) methodologies. These peptides oligomers were modelled as potential inhibitors of this enzyme through coiled–coil interactions. The dimer, trimer and tetramer aggregate energies for these synthetic peptides were calculated and their stability discussed. One of these peptides, EAA26 shows some propensity to form a tetrameric structure when attached to the calix[4]arene frame through a succinic linker; the possibility to form the quadruple peptide helix, an entity which was not obtained from peptide systems, was evaluated. q 2005 Elsevier B.V. All rights reserved.
    Journal of Molecular Structure THEOCHEM 11/2005; · 1.37 Impact Factor
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    ABSTRACT: Several synthetic 23–26 aminoacids long peptides were previously prepared as inhibitors of HIV-1 integrase (IN). These peptides were derived from the amphipathic a4 helix of the viral enzyme that plays a crucial role in the integration process of the viral DNA into the host chromosomes. It has been shown that the a-4 helix interacts with the viral DNA through several of its hydrophilic residues and it has been suggested that it could be implicated in the enzyme oligomerization through hydrophobic interactions between several of its hydrophobic residues. The inhibition observed in presence of the peptides is probably due to peptide/IN coiled-coil interactions as both counterparts exhibit hydrophobic heptad repeats characterizing coiled-coil motifs. In this study, molecular modeling calculations were run in order to evaluate the binding of dimer type peptide inhibitors to the a-4 helix. Glutaric dialdehyde was used in the modeling study as the crosslinking agent of peptide dimers. The final goal is the development of more efficient inhibitors against HIV-1 IN. q 2005 Elsevier B.V. All rights reserved.
    Journal of Molecular Structure THEOCHEM 08/2005; · 1.37 Impact Factor

Publication Stats

839 Citations
379.75 Total Impact Points

Institutions

  • 2007–2012
    • Ecole normale supérieure de Cachan
      Cachon, Île-de-France, France
  • 1992–2012
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1990–2006
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 1999
    • Institute of Physical and Chemical Biology
      Lutetia Parisorum, Île-de-France, France
  • 1991–1992
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 1988
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
  • 1987
    • Institut de France
      Lutetia Parisorum, Île-de-France, France