Publications by authors named "Stephane Téletchéa"

21 Publications

  • Page 1 of 1

The twin cytokines interleukin-34 and CSF-1: masterful conductors of macrophage homeostasis.

Theranostics 2021 1;11(4):1568-1593. Epub 2021 Jan 1.

Université de Nantes, Institut de Cancérologie de l'Ouest, Saint-Herblain, F-44805, France.

Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.
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http://dx.doi.org/10.7150/thno.50683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778581PMC
January 2021

STOREFISH 2.0: a database on the reproductive strategies of teleost fishes.

Database (Oxford) 2020 11;2020

University of Lorraine, INRAE, UR AFPA, 2 avenue de la Forêt de Haye - BP 20163 , F-54000, Vandoeuvre-lès-Nancy Cedex, France.

Teleost fishes show the most outstanding reproductive diversity of all vertebrates. Yet to date, no one has been able to decisively explain this striking variability nor to perform large-scale phylogenetic analyses of reproductive modes. Here, we describe STrategies Of REproduction in FISH (STOREFISH) 2.0, an online database easing the sharing of an original data set on reproduction published in 2007, enriched with automated data extraction and presentation to display the knowledge acquired on temperate freshwater fish species. STOREFISH 2.0 contains the information for 80 freshwater fish species and 50 traits from the analysis of 1219 references. It is anticipated that this new database could be useful for freshwater biodiversity research, conservation, assessment and management. Database URL: www.storefish.org.
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http://dx.doi.org/10.1093/database/baaa095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678788PMC
November 2020

Access to Galectin-3 Inhibitors from Chemoenzymatic Synthons.

J Org Chem 2020 12 17;85(24):16099-16114. Epub 2020 Nov 17.

Université de Nantes, CNRS, Unité Fonctionnalité et Ingénierie des Protéines (UFIP), UMR 628, F-44000 Nantes, France.

Chemoenzymatic strategies are useful for providing both regio- and stereoselective access to bioactive oligosaccharides. We show herein that a glycosynthase mutant of a α-glycosidase can react with unnatural glycosides such as 6-azido-6-deoxy-d-glucose/glucosamine to lead to β-d-galactopyranosyl-(1→3)-d-glucopyranoside or β-d-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-d-glucopyranoside derivatives bearing a unique azide function. Taking advantage of the orthogonality between the azide and the hydroxyl functional groups, the former was next selectively reacted to give rise to a library of galectin-3 inhibitors. Combining enzyme substrate promiscuity and bioorthogonality thus appears as a powerful strategy to rapidly access to sugar-based ligands.
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http://dx.doi.org/10.1021/acs.joc.0c01927DOI Listing
December 2020

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Am J Hum Genet 2019 11 17;105(5):1040-1047. Epub 2019 Oct 17.

CHU Nantes, Service de génétique médicale, F-44000 Nantes, France. Electronic address:

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849359PMC
November 2019

DockNmine, a Web Portal to Assemble and Analyse Virtual and Experimental Interaction Data.

Int J Mol Sci 2019 Oct 12;20(20). Epub 2019 Oct 12.

UFIP, Université de Nantes, UMR CNRS 6286, 2 rue de la Houssinière, 44322 Nantes, France.

Scientists have to perform multiple experiments producing qualitative and quantitative data to determine if a compound is able to bind to a given target. Due to the large diversity of the potential ligand chemical space, the possibility of experimentally exploring a lot of compounds on a target rapidly becomes out of reach. Scientists therefore need to use virtual screening methods to determine the putative binding mode of ligands on a protein and then post-process the raw docking experiments with a dedicated scoring function in relation with experimental data. Two of the major difficulties for comparing docking predictions with experiments mostly come from the lack of transferability of experimental data and the lack of standardisation in molecule names. Although large portals like PubChem or ChEMBL are available for general purpose, there is no service allowing a formal expert annotation of both experimental data and docking studies. To address these issues, researchers build their own collection of data in flat files, often in spreadsheets, with limited possibilities of extensive annotations or standardisation of ligand descriptions allowing cross-database retrieval. We have conceived the dockNmine platform to provide a service allowing an expert and authenticated annotation of ligands and targets. First, this portal allows a scientist to incorporate controlled information in the database using reference identifiers for the protein (Uniprot ID) and the ligand (SMILES description), the data and the publication associated to it. Second, it allows the incorporation of docking experiments using forms that automatically parse useful parameters and results. Last, the web interface provides a lot of pre-computed outputs to assess the degree of correlations between docking experiments and experimental data.
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http://dx.doi.org/10.3390/ijms20205062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829441PMC
October 2019

Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors.

Int J Mol Sci 2019 Sep 23;20(19). Epub 2019 Sep 23.

CEISAM UMR CNRS 6230, UFR Sciences et Techniques, Université de Nantes, 44322 Nantes CEDEX 3, France.

The enzyme phospholipase C gamma 1 (PLCγ1) has been identified as a potential drug target of interest for various pathological conditions such as immune disorders, systemic lupus erythematosus, and cancers. Targeting its SH3 domain has been recognized as an efficient pharmacological approach for drug discovery against PLCγ1. Therefore, for the first time, a combination of various biophysical methods has been employed to shed light on the atomistic interactions between PLCγ1 and its known binding partners. Indeed, molecular modeling of PLCγ1 with SLP76 peptide and with previously reported inhibitors (ritonavir, anethole, daunorubicin, diflunisal, and rosiglitazone) facilitated the identification of the common critical residues (Gln805, Arg806, Asp808, Glu809, Asp825, Gly827, and Trp828) as well as the quantification of their interaction through binding energies calculations. These features are in agreement with previous experimental data. Such an in depth biophysical analysis of each complex provides an opportunity to identify new inhibitors through pharmacophore mapping, molecular docking and MD simulations. From such a systematic procedure, a total of seven compounds emerged as promising inhibitors, all characterized by a strong binding with PLCγ1 and a comparable or higher binding affinity to ritonavir (∆G < -25 kcal/mol), one of the most potent inhibitor reported till now.
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http://dx.doi.org/10.3390/ijms20194721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801593PMC
September 2019

Development of a Sensitive Microarray Platform for the Ranking of Galectin Inhibitors: Identification of a Selective Galectin-3 Inhibitor.

Chembiochem 2017 12 20;18(24):2428-2440. Epub 2017 Nov 20.

Faculté des Sciences et des Techniques, Unité Fonctionnalité et Ingénierie des Protéines (UFIP), Université de Nantes, UMR CNRS 6286, 2, chemin de la Houssinière, B. P. 92208, 44322, Nantes Cedex 3, France.

Glycan microarrays are useful tools for lectin glycan profiling. The use of a glycan microarray based on evanescent-field fluorescence detection was herein further extended to the screening of lectin inhibitors in competitive experiments. The efficacy of this approach was tested with 2/3'-mono- and 2,3'-diaromatic type II lactosamine derivatives and galectins as targets and was validated by comparison with fluorescence anisotropy proposed as an orthogonal protein interaction measurement technique. We showed that subtle differences in the architecture of the inhibitor could be sensed that pointed out the preference of galectin-3 for 2'-arylamido derivatives over ureas, thioureas, and amines and that of galectin-7 for derivatives bearing an α substituent at the anomeric position of glucosamine. We eventually identified a diaromatic oxazoline as a highly specific inhibitor of galectin-3 versus galectin-1 and galectin-7.
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http://dx.doi.org/10.1002/cbic.201700544DOI Listing
December 2017

Biophysical and structural characterization of mono/di-arylated lactosamine derivatives interaction with human galectin-3.

Biochem Biophys Res Commun 2017 07 26;489(3):281-286. Epub 2017 May 26.

Unité Fonctionnalité et Ingénierie des Protéines, UMR CNRS, 6286, Université des Sciences et Techniques de Nantes, 2 rue de la Houssinière, BP92208, F-44322 Nantes Cedex, France; Laboratoire de Glycochimie, des Antimicrobiens et des Agroressources, UMR CNRS 7378, Institut de Chimie de Picardie, Université de Picardie Jules Verne, 33 rue Saint-Leu, F-80039 Amiens Cedex, France. Electronic address:

Combination of biophysical and structural techniques allowed characterizing and uncovering the mechanisms underlying increased binding affinity of lactosamine derivatives for galectin 3. In particular, complementing information gathered from X-ray crystallography, native mass spectrometry and isothermal microcalorimetry showed favorable enthalpic contribution of cation-π interaction between lactosamine aryl substitutions and arginine residues from the carbohydrate recognition domain, which resulted in two log increase in compound binding affinity. This incrementing strategy allowed individual contribution of galectin inhibitor moieties to be dissected. Altogether, our results suggest that core and substituents of these saccharide-based inhibitors can be optimized separately, providing valuable tools to study the role of galectins in diseases.
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http://dx.doi.org/10.1016/j.bbrc.2017.05.150DOI Listing
July 2017

IL-34 and M-CSF form a novel heteromeric cytokine and regulate the M-CSF receptor activation and localization.

Cytokine 2015 Dec 19;76(2):170-181. Epub 2015 Jun 19.

INSERM, UMR 957, Equipe Ligue 2012, Nantes F-44035, France; Université de Nantes, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, France; Centre hospitalier universitaire de Nantes, France. Electronic address:

Interleukin-34 (IL-34) is a newly-discovered homodimeric cytokine that regulates, like Macrophage Colony-Stimulating Factor (M-CSF), the differentiation of the myeloid lineage through M-CSF receptor (M-CSFR) signaling pathways. To date, both cytokines have been considered as competitive cytokines with regard to the M-CSFR. The aim of the present work was to study the functional relationships of these cytokines on cells expressing the M-CSFR. We demonstrate that simultaneous addition of M-CSF and IL-34 led to a specific activation pattern on the M-CSFR, with higher phosphorylation of the tyrosine residues at low concentrations. Similarly, both cytokines showed an additive effect on cellular proliferation or viability. In addition, BIAcore experiments demonstrated that M-CSF binds to IL-34, and molecular docking studies predicted the formation of a heteromeric M-CSF/IL-34 cytokine. A proximity ligation assay confirmed this interaction between the cytokines. Finally, co-expression of the M-CSFR and its ligands differentially regulated M-CSFR trafficking into the cell. This study establishes a new foundation for the understanding of the functional relationship between IL-34 and M-CSF, and gives a new vision for the development of therapeutic approaches targeting the IL-34/M-CSF/M-CSFR axis.
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http://dx.doi.org/10.1016/j.cyto.2015.05.029DOI Listing
December 2015

Protein flexibility in the light of structural alphabets.

Front Mol Biosci 2015 27;2:20. Epub 2015 May 27.

Institut National de la Santé et de la Recherche Médicale U 1134 Paris, France ; UMR_S 1134, DSIMB, Université Paris Diderot, Sorbonne Paris Cite Paris, France ; Institut National de la Transfusion Sanguine, DSIMB Paris, France ; UMR_S 1134, DSIMB, Laboratory of Excellence GR-Ex Paris, France.

Protein structures are valuable tools to understand protein function. Nonetheless, proteins are often considered as rigid macromolecules while their structures exhibit specific flexibility, which is essential to complete their functions. Analyses of protein structures and dynamics are often performed with a simplified three-state description, i.e., the classical secondary structures. More precise and complete description of protein backbone conformation can be obtained using libraries of small protein fragments that are able to approximate every part of protein structures. These libraries, called structural alphabets (SAs), have been widely used in structure analysis field, from definition of ligand binding sites to superimposition of protein structures. SAs are also well suited to analyze the dynamics of protein structures. Here, we review innovative approaches that investigate protein flexibility based on SAs description. Coupled to various sources of experimental data (e.g., B-factor) and computational methodology (e.g., Molecular Dynamic simulation), SAs turn out to be powerful tools to analyze protein dynamics, e.g., to examine allosteric mechanisms in large set of structures in complexes, to identify order/disorder transition. SAs were also shown to be quite efficient to predict protein flexibility from amino-acid sequence. Finally, in this review, we exemplify the interest of SAs for studying flexibility with different cases of proteins implicated in pathologies and diseases.
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http://dx.doi.org/10.3389/fmolb.2015.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445325PMC
June 2015

Novel RANK antagonists for the treatment of bone-resorptive disease: theoretical predictions and experimental validation.

J Bone Miner Res 2014 Jun;29(6):1466-77

INSERM, UMR 957, Equipe labellisée LIGUE 2012, Université de Nantes, Laboratory of the Physiopathology of Bone Resorption and Therapy of Primary Bone Tumors (LPRO), Nantes, France.

Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody-based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure- and knowledge-based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone disease.
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http://dx.doi.org/10.1002/jbmr.2170DOI Listing
June 2014

Osteoprotegerin: multiple partners for multiple functions.

Cytokine Growth Factor Rev 2013 Oct 1;24(5):401-9. Epub 2013 Jul 1.

INSERM, UMR957, Nantes F-44035, France; Université de Nantes, Nantes atlantique universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes F-44035, France; CHU, Hôtel Dieu, Nantes, France. Electronic address:

Osteoprotegerin (OPG) is an essential secreted protein in bone turnover due to its role as a decoy receptor for the Receptor Activator of Nuclear Factor-kB ligand (RANKL) in the osteoclasts, thus inhibiting their differentiation. However, there are additional ligands of OPG that confer various biological functions. OPG can promote cell survival, cell proliferation and facilitates migration by binding TNF-related apoptosis inducing ligand (TRAIL), glycosaminoglycans or proteoglycans. A large number of in vitro, pre-clinical and clinical studies provide evidences of OPG involvement in vascular, bone, immune and tumor biology. This review describes an overview of the different OPG ligands regulating its biological functions.
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http://dx.doi.org/10.1016/j.cytogfr.2013.06.001DOI Listing
October 2013

Automatic modeling of mammalian olfactory receptors and docking of odorants.

Protein Eng Des Sel 2012 Aug 12;25(8):377-86. Epub 2012 Jun 12.

INRA, Mathématique, Informatique et Génome UR1077, 78350 Jouy-en-Josas, France.

We present a procedure that (i) automates the homology modeling of mammalian olfactory receptors (ORs) based on the six three-dimensional (3D) structures of G protein-coupled receptors (GPCRs) available so far and (ii) performs the docking of odorants on these models, using the concept of colony energy to score the complexes. ORs exhibit low-sequence similarities with other GPCR and current alignment methods often fail to provide a reliable alignment. Here, we use a fold recognition technique to obtain a robust initial alignment. We then apply our procedure to a human OR that we have previously functionally characterized. The analysis of the resulting in silico complexes, supported by receptor mutagenesis and functional assays in a heterologous expression system, suggests that antagonists dock in the upper part of the binding pocket whereas agonists dock in the narrow lower part. We propose that the potency of agonists in activating receptors depends on their ability to establish tight interactions with the floor of the binding pocket. We developed a web site that allows the user to upload a GPCR sequence, choose a ligand in a library and obtain the 3D structure of the free receptor and ligand-receptor complex (http://genome.jouy.inra.fr/GPCRautomodel).
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http://dx.doi.org/10.1093/protein/gzs037DOI Listing
August 2012

A functional, new short isoform of death receptor 4 in Ewing's sarcoma cell lines may be involved in TRAIL sensitivity/resistance mechanisms.

Mol Cancer Res 2012 Mar 18;10(3):336-46. Epub 2012 Jan 18.

1INSERM, Equipe labellisee LIGUE 2012 UMR 957, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, EA3822, Nantes, France.

Ewing's sarcoma (ES) is a high-grade neoplasm arising in bones of children and adolescents. Survival rate decreases from greater than 50% to only 20% after 5 years for patients not responding to treatment or presenting metastases at diagnosis. TRAIL, which has strong antitumoral activity, is a promising therapeutic candidate. To address TRAIL sensitivity, 7 human ES cell lines were used. Cell viability experiments [3'[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro-)benzene sulfonic acid hydrate (XTT) assay] showed that 4 of the 7 ES cell lines were resistant to TRAIL. Western blotting and flow cytometry analyses revealed that DR5 was uniformly expressed by all ES cell lines, whereas DR4 levels were higher in sensitive cell lines. In TRAIL-sensitive TC-71 cells, knockdown of TNFRSF10A/DR4 by short hairpin RNA (shRNA) was associated with a loss of sensitivity to TRAIL, in spite of DR5 presence. Interestingly, we identified a new transcript variant that results from an alternative splicing and encodes a 310-amino acid protein which corresponds to the 468 aa of DR4 original isoform but truncated of aa 11 to 168 within the extracellular TRAIL-binding domain. According to modeling studies, the contact of this new DR4 isoform (bDR4) with TRAIL seemed largely preserved. The overexpression of bDR4 in a TRAIL-resistant cell line restored TRAIL sensitivity. TRAIL resensitization was also observed after c-FLIP knockdown by shRNA in two TRAIL-resistant cell lines, as shown by XTT assay and caspase-3 assay. The results presented in this study showed that DR4, both as the complete form or as its new short isoform, is involved in TRAIL sensitivity in ES.
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http://dx.doi.org/10.1158/1541-7786.MCR-11-0390DOI Listing
March 2012

TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment.

Am J Cancer Res 2012 9;2(1):45-64. Epub 2011 Oct 9.

Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) has been reported to specifically induce malignant cell death being relatively nontoxic to normal cells. Since its identification 15 years ago, the antitumor activity and therapeutic value of TRAIL have been extensively studied. Five receptors quickly emerged, two of them being able to induce programmed cell death in tumor cells. This review takes a comprehensive look at this ligand and its receptors, and its potential role in primary bone tumors (osteosarcoma and Ewing's sarcoma) therapy. The main limit of clinical use of TRAIL being the innate or acquired resistance mechanisms, different possibilities to sensitize resistant cells are discussed in this review, together with the impact of bone microenvironment in the regulation of TRAIL activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236571PMC
October 2012

Cisplatin adducts on a GGG sequence within a DNA duplex studied by NMR spectroscopy and molecular dynamics simulations.

Chemistry 2009 Nov;15(45):12320-37

Laboratoire de Chimie et Biochimie, Pharmacologiques et Toxicologiques, Université Paris Descartes, UMR 8601 CNRS, 45 rue des Saints-Pères, 75270 Paris (France), Fax: (+33) 142-86-83-87.

The antitumor drug cisplatin(cis-[PtCl2(NH3)2]) reacts with cellular DNA to form GG intrastrand adducts between adjacent guanines as predominant lesions. GGG sites have been shown to be hotspots of platination. To study the structural perturbation induced by binding of cisplatin to two adjacent guanines of a GGG trinucleotide,we examined here the decanucleotide duplex d[(G1C2C3G*4 G*5 G6T7-C8G9C10).d(G11C12G13A14C15C16C17G18-G19C20)] (dsCG*G*G) intrastrand cross-linked at the G* guanines by cis-{Pt(NH3)2}2+ using NMR spectroscopy and molecular dynamics (MD) simulations.The NMR spectra of dsCG*G*G were found to be similar to those of previously characterized DNA duplexes cross-linked by cisplatin at apyG*G*X site (py=pyrimidine; X=C,T, A). This similarity of NMR spectra indicates that the base at the 3'-side of the G*G*-Pt cross-link does not affect the structure to a large extent. An unprecedented reversible isomerization between the duplex dsCG*G*G (bearing a G*4 G*5 -Pt chelate) and duplex dsGG*G*T (bearing a G*5 G*6 -Pt chelate)was observed, which yielded a 40:60 equilibrium between the two intrastrand GG-Pt cross-links. No formation of interstrand cross-links was observed.NMR spectroscopic data of dsCG*G*G indicated that the deoxyribose of the 5'-G* adopts an N-type conformation, and the cytidines C3, C15,and C16 have average phase angles intermediate between S and N. The NMR spectroscopic chemical shifts of dsGG*G*T showed some fundamental differences to those of pyG*G*-platinum adducts but were in agreement with the NMR spectra reported previously for the DNA duplexes crosslinked at an AG*G*C sequence by cisplatin or oxaliplatin. The presence of apurine instead of a pyrimidine at the 5'-side of the G*G* cross-link seems therefore to affect the structure of the XG* step significantly.
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http://dx.doi.org/10.1002/chem.200901158DOI Listing
November 2009

Factor VIII-von Willebrand factor complex inhibits osteoclastogenesis and controls cell survival.

J Biol Chem 2009 Nov 16;284(46):31704-13. Epub 2009 Sep 16.

INSERM U957, Université de Nantes, Nantes Atlantique Universités, Laboratoire de Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Nantes F-44035, France.

Factor VIII-von Willebrand factor (FVIII.vWF) complex, a molecule involved in coagulation, can be physically associated with osteoprotegerin (OPG). OPG is an anti-osteoclastic protein and a soluble receptor for the proapoptotic protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), suggesting a potential role of FVIII.vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII.vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII.vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII.vWF complex bound to RANKL, whereas recombinant FVIII and vWF did not. By modeling, we showed that the OPG binding domain to the A1 domain of vWF was closely located and partially overlapped to its binding site to RANKL. Then, we demonstrated that FVIII.vWF complex cancelled the inhibitory activity of OPG on TRAIL-induced apoptosis and characterized interactions between these molecules. The present work evidenced a direct activity of FVIII.vWF complex on osteoclasts and on induced cell apoptosis, pointing out its potential involvement in physiological bone remodeling or in bone damages associated with severe hemophilia and cancer development.
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http://dx.doi.org/10.1074/jbc.M109.030312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797241PMC
November 2009

A pyrazolato-bridged dinuclear platinum(II) complex induces only minor distortions upon DNA-binding.

Chemistry 2006 May;12(14):3741-53

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université René Descartes, UMR 8601 CNRS, 45, rue des Saints-Pères, 75270 Paris Cedex 06, France.

The cytotoxic, pyrazolato-bridged dinuclear platinum(II) complex [(cis-{Pt(NH3)2})2(mu-OH)(mu-pz)]2+ (pz=pyrazolate) has been found to cross-link two adjacent guanines of a double-stranded DNA decamer without destabilizing the duplex and without changing the directionality of the helix axis. A 1H NMR study of the oligonucleotide d(CTCTG*G*TCTC)-d(GAGACCAGAG), cross-linked at the two G* guanines by [(cis-{Pt(NH3)2})2(mu-pz)]3+, and molecular dynamics simulations of the explicitly solvated duplex were performed to characterize the structural details of the adduct. The dinuclear platinum cross-link unwinds the helix by approximately 15 degrees , that is, to a similar extent as the widely used antitumor drug cisplatin, but, in contrast to the latter, induces no significant bend in the helix axis. The Watson-Crick base-pairing remains intact, and the melting temperature of the duplex is unaffected by the cross-link. The helical twist is considerably reduced between the two platinated bases, as becomes manifest in an unusually short sequential H1'-H1' distance. This unwinding also affects the sugar ring of the guanosine in the 3'-position to the cross-link, which presents an N<-->S equilibrium. This is the first cytotoxic platinum complex that has been successfully designed by envisioning the structural consequences of its binding to DNA.
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http://dx.doi.org/10.1002/chem.200500923DOI Listing
May 2006

Recognition complex between the HMG domain of LEF-1 and its cognate DNA studied by molecular dynamics simulations with explicit solvation.

J Biomol Struct Dyn 2005 Aug;23(1):1-11

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Universite Rene Descartes, 75270 Paris Cedex 06, France.

Molecular dynamics simulations of the complex formed between the HMG box of the lymphoid enhancer-binding factor (LEF-1) and its cognate DNA duplex were carried out with explicit inclusion of water. The simulation started with an NMR-based model (pdb code 2LEF) and the dynamics was pursued for 10 nanoseconds without constraints. It revealed that water intervenes in many ionic/polar interactions, establishing in particular local equilibria between direct and water-mediated hydrogen bonds, and thus increasing the entropy of the complex. Quite unexpectedly, the simulation indicated that a binding pocket for a specific water molecule may be reversibly formed at the apex of the bend induced in the DNA helix by LEF-1 binding, where a methionine side chain intercalates between two destacked adenines. We observed that the specific water molecule can temporarily replace the intercalated S-CH(3) group, acting as a sort of "extension" of the side chain. The residence time of this water molecule was about 3.5 ns. Simulations of the cognate DNA alone showed that this sequence has no intrinsic tendency to bend; therefore, the bending occurs solely as a consequence of the recognition, following the "induced-fit" mechanism.
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http://dx.doi.org/10.1080/07391102.2005.10507042DOI Listing
August 2005

Discrimination between BI and BII conformational substates of B-DNA based on sugar-base interproton distances.

J Biomol Struct Dyn 2004 Feb;21(4):489-94

Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Universite Rene Descartes, 45, rue des Saints-Peres, 75270 Paris Cedex 06, France.

Molecular dynamics (MD) simulations of four water-solvated DNA duplexes were used to generate a database of approximately 27000 dinucleotide conformations. Analyzing this database, we investigated the relationship between so-called BI-BII transitions and short-range interproton distances. Four H-H distances were found particularly sensitive to BI-BII transitions: internucleotide H1'(n)-H68(n+1), H2'(n)-H68(n+1), and H2"(n)-H68(n+1), and intranucleotide H2"(n)-H68(n). Determination of these distances using classical NOESY spectroscopy can thus provide valuable indications on the existence of BII substates, complementing the existing method based on (31)P chemical shifts and (31)P-(1)H spin-spin coupling constants.
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http://dx.doi.org/10.1080/07391102.2004.10506942DOI Listing
February 2004

Motifs in nucleic acids: molecular mechanics restraints for base pairing and base stacking.

J Comput Chem 2003 Jan;24(1):1-9

Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.

In building and refining nucleic acid structures, it is often desirable to enforce particular base pairing and/or base stacking interactions. Energy-based modeling programs with classical molecular mechanics force fields do not lend themselves to the easy imposition of penalty terms corresponding to such restraints, because the requirement that two bases lie in or near the same plane (pairing) or that they lie in parallel planes (stacking) cannot be easily expressed in terms of traditional interactions involving two atoms (bonds), three atoms (angles), or four atoms (torsions). Here we derive expressions that define a collection of pseudobonds and pseudoangles through which molecular mechanics restraints for base pairing and stacking can be imposed. We have implemented these restraints into the JUMNA package for modeling DNA and RNA structures. JUMNA scripts can specify base pairing with a variety of standard geometries (Watson-Crick, Hoogsteen, wobble, etc.), or with user-defined geometries; they can also specify stacking arrangements. We have also implemented "soft-core" functions to modify van der Waals and electrostatic interactions to avoid steric conflicts in particularly difficult refinements where two backbones need to pass through one another. Test cases are presented to show the utility of the method. The restraints could be adapted for implementation in other molecular mechanics packages.
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http://dx.doi.org/10.1002/jcc.10173DOI Listing
January 2003