Дисертації з теми "G quadruplex binding ligand"
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Marchand, Adrien. "Mass Spectrometry Study of G-Quadruplex Nucleic Acids : folding Pathways and Ligand Binding Modes." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0196/document.
Повний текст джерелаA G-quadruplex (G4) is a non-canonical nucleic acids structure formed by guanine-rich sequences. Some G4s are polymorphic, a given sequence can form G4s of different topologies. G4s are proposed to be biological regulators because they are found in key regions of the genome, for example, ingene promoters or at the telomeres. Stabilizing G4s formed in those regions as compared to the duplex form is a strategy to fight cancer. To do so, specific and affine ligands are used. Ligand design usually implies the optimization of large aromatic planes to π-π stack on external G-quartets. However, if this was the only binding mode, all ligands would bind with similar affinities to all G4s.To characterize which structures should be targeted and how the ligands interact with these structures, we used native mass spectrometry (MS).First, we developed a MS-compatible sample preparation method in KCl conditions in which G4s are folded with similar topologies as compared to those obtained in biologically relevant conditions. Then, we characterized the K+ binding equilibria and G4s folding pathways. This folding pathway involves the presence of a dead-end constituted by antiparallel G4s with either 1- or 2-K+ cations that are folded first. Finally, our ligand binding studies showed that some of the most affine ligands can influence G4’sstructures, as probed by the number of K+ ions bound. Ligands Phen-DC3, 360A and PDS are able to shift the equilibria towards the 1-K+ antiparallel G4s. The formation of antiparallel with 2-K+ complexes is induced by the cooperative binding of two Cu-ttpy ligands. Our results demonstrate the importance to characterize ternary complex stoichiometries (G4:ligand:K+) as obtained from native mass spectrometry
Bai, Liping. "The noncovalent binding of benzophenathridine alkaloids to double-stranded, bulged and G-quadruplex DNA." HKBU Institutional Repository, 2008. http://repository.hkbu.edu.hk/etd_ra/910.
Повний текст джерелаBright, Lois Eleanor. "Ligands and complexes for non-covalent binding to G-quadruplex DNA structures." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7457/.
Повний текст джерелаPipier, Angélique. "Etudes des G-quadruplexes : impact de la stabilisation par des ligands en tant qu'agents anti-cancéreux et identification des protéines associées régulant leur métabolisme." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30118.
Повний текст джерелаG-quadruplexes (or G4) are non-canonical structures of nucleic acid formed from guanine-rich sequences. G4 are stable structures, present throughout the genome and could be folded into different conformations. G4 formation can regulate, positively or negatively, different cellular processes such as transcription, replication, RNA transactions and mitochondrial mechanisms. All these processes require the recruitment of proteins able to modulate the formation of these structures. Indeed, some proteins, such as BLM, WRN or DHX36 helicases, are able to unwind G4 while others, like nucleolin (NCL), bind to and stabilize G4. Finally, G4 ligands, small molecules stabilizing G4, can impact various processes in which G4 are involved; in particular, they can cause repression of oncogene expression and lead to genomic instability. Thus, G4 ligands are considered to be potential anti-cancer agents. My thesis work focuses on several issues concerning G4: 1/ the improvement of G4 ligands and their characterization; 2/ the deciphering of the mechanisms inducing genomic instability following G4 stabilization by ligands; 3/ the identification of proteins able to bind to G4 (or GBPs for "G4 Binding Proteins"). Through biochemical and biophysical experiments, I have participated in the characterization of porphyrin-derived ligands. In the case of the AuMA ligand, I showed an increase in both G4 stabilization capacity and G4 specificity, compared to other porphyrin-derived molecules. This molecule therefore represents a better therapeutic potential than TMPyP4, a widely characterized ligand from which it is derived. I have also studied the genomic instability due to G4 stabilization using the pyridostatin ligand and the CX5461 ligand, currently in Phase II of a clinical trial. These ligands induce DNA double-strand breaks (or DSBs) dependent on transcription by RNA polymerase II and partly due to the transcriptional pausing. DSBs are initiated by the activity of Topoisomerases II, enzymes involved in the resolution of DNA topological stresses due to transcription and replication. These results show the significant role of transcription in the induction of genomic instability and open up new therapeutic approaches in the treatment of cancers in which these proteins are overexpressed or by combining them with other chemotherapies such as etoposide to increase their cytotoxic potential. I have studied G4-binding proteins using constrained structures, blocked in a particular conformation, by developing a protocol for the detection of GBPs through Pull-Down experiments followed by mass spectrometry analysis. These results, validated by the binding to G4 of proteins already identified and characterized such as WRN, DHX36 or CNBP, allow the identification of 425 GBP. Thus, I have highlighted new GBPs involved in various cellular processes such as replication, DNA repair, transcription and RNA metabolism. Aside, the study of CNBP protein in a zebrafish model has shown that the regulation of G4 in vivo affects transcription and embryonic development, reinforcing the role of G4 in whole living organisms. My work contributes to extend the knowledge of G4 and their ligands, particularly the mechanisms of action of G4 during transcription, and is opening up new therapeutic perspectives
Schouten, James Alexander. "Probing selective G-quadruplex binding using peptide motifs." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620018.
Повний текст джерелаKerkour, Abdelaziz. "Study of DNA G-quadruplex structures by Nuclear Magnetic Resonance (NMR)." Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0292/document.
Повний текст джерелаG-quadruplexes (G4) are non-canonical nucleic acid structures formed by G-rich sequences mainly localized in telomeres and promoter regions of oncogenes. They are built from the stacking of several G-quartets in the presence of cations. Using NMR spectroscopy, we have characterized the interaction between the TAP ligand and the human telomeric G4 formed by the sequence d(AG3(T2AG3)3). CD and 1D 1H NMR spectroscopy were used to follow the interaction between the two partners. 2D NMR was used to assign unambiguously all 1H resonances in the complex and to explore the binding site. A model depicting the interaction of TAP with 22AG in grooves and loops was generated. Another part of this work consists in the study of tetramolecular G4 formed by TG4T and its interaction with G4 ligands by in-cell NMR. 1H-15N HMQC spectra were performed inside Xenopus laevis and HeLa cell lysates compared to those observed in vitro conditions showing a good stability of G4 inside the cell. Furthermore, the interaction of d[TG4T]4 with three G4 specific ligands presenting different mode of interaction was also investigated. The ligand 360A showed a promising behavior. Finally, in the last part, different sequences of Kras promoter were screened by NMR to select good candidates for high resolution structure determination. Two different sequences were selected and characterized by CD spectroscopy. The stabilization of G4 structures formed by these sequences in interaction with different ligands was also investigated. A 1D 1H NMR titration between Braco19 and 22RT showed an interesting behavior of k-ras G4 by the formation of intermediate species upon the addition of Braco19
Campbell, Nancy Husni. "Crystallographic and Molecular Modelling Studies of G-Quadruplex-Ligand complexes." Thesis, University College London (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515056.
Повний текст джерелаKoirala, Deepak P. "Mechanochemistry, Transition Dynamics and Ligand-Induced Stabilization of Human Telomeric G-Quadruplexes at Single-Molecule Level." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1397919270.
Повний текст джерелаQin, Yong. "Targeting the Promoter Regions of PDGF Ligand and Receptor." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/194387.
Повний текст джерелаPatel, Sachin Dinesh. "Studies on a designed G-quadruplex binding protein that inhibits human telomerase." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620939.
Повний текст джерелаEngelhard, David Maximilian. "Synthesis and coordination chemistry of tetradentate chelators based on ligand-appended G-quadruplex structures." Doctoral thesis, Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://hdl.handle.net/11858/00-1735-0000-002B-7CD4-7.
Повний текст джерелаRangan, Anupama. "Structural studies of nucleic acids dynamics of RNA pseudoknots and G-quadruplex DNA-ligand interactions /." Access restricted to users with UT Austin EID, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3077362.
Повний текст джерелаEvans, Philip James. "Multivariate mapping of G protein-coupled receptor ligand binding sites." Thesis, University of Portsmouth, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494433.
Повний текст джерелаRay, Sujay. "Interactions of DNA binding proteins with G-Quadruplex structures at the single molecule level." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1415185457.
Повний текст джерелаAbd, Karim Nurul Huda. "Studies towards elucidating the binding modes between metal-salphen complexes and G-quadruplex DNA." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9658.
Повний текст джерелаMusetti, Caterina Livia. "Heterocyclic Cations as Potential Anticancer Agents: An Approach that Targets G-quadruplex with Different Binding Modes." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/chemistry_theses/26.
Повний текст джерелаLefebvre, Joël. "Outils moléculaires pour l'étude des G-quadruplex au sein du génome." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS536/document.
Повний текст джерелаDeoxyribonucleic acid has different structures in human beings. The most known is the double helix but a lot of secondary structures exist and particularly G-quadruplex. It consists of guanine-rich nucleic acid sequences. The association of four guanines through hydrogen bonds forms a plan called G-quartet. This set of hydrogen bonds is called Hoogsteen base pairs. The stacking of at least two quartets around a monovalent cation like potassium or sodium establishes the G-quadruplex. These structures have been much studied over the past twenty years. They are involved in numerous biological mechanisms like replication, transcription, translation and also telomere maintenance. G-quadruplex presence can cause an important genetic as well as epigenetic instability. That is why many methods have been developed in order to localize these structures and to understand their role in vivo. To this end, a broad panel of molecular tools has been used. However, it is still difficult to bring an answer to all the questions about the involvement of G-quadruplex at the genomic level with this panel. In this thesis work, we developed new molecular tools able to target selectively G-quadruplex in a complex biological medium from two benchmark ligands, PhenDC3 and PDC, which have very good affinity and selectivity for G-quadruplex.On the one hand, functionalized ligands have been synthetized with a biotin and/or a photoactivatable group in order to trap and pull-down G-quadruplex in various cellular contexts. On the other hand, derivative compounds which are able to be functionalized in cellulo by bioorthogonal reactions have been obtained. Once the compound interacts with its cellular target, a function (fluorophore or biotin) can be added through an orthogonal reaction. The new panel of compounds has been evaluated by biophysical techniques, FRET-melting experiment and FID assay, in order to determine their affinity to G-quadruplex and their selectivity. We proposed a relation between the two biophysical experiments in order to have a good ranking of ligands for G-quadruplex structures.One of the most important objectives of this work was to localize G-quadruplex ligands in human cancer cells. First, a complete study in fixed cells has been performed using two reactions of click chemistry: reaction of copper-catalyzed-alkyne-azide-cycloaddition (CuAAC) and reaction of strain-promoted alkyne-azide cycloaddition (SPAAC). Secondly, the study has been pursued in living cells using SPAAC reaction because of the toxicity of copper in cells.These compounds have also been used to extract G-quadruplex from biological systems with cyclooctyne-coated magnetic beads. However, results obtained in this preliminary study are not decisive so it could be interesting to optimize the system before concluding
Hampel, Sonja Margarethe. "Design and synthesis of G-quadruplex binding small molecules and their evaluation as anti-cancer agents." Thesis, University of London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.535503.
Повний текст джерелаAsamitsu, Sefan. "Toward Elucidating the Function of Non-canonical DNA Structures using Selective DNA-interacting Ligands." Kyoto University, 2019. http://hdl.handle.net/2433/242622.
Повний текст джерелаLee, Sang C., Jack Zhang, Josh Strom, Danzhou Yang, Thai Nho Dinh, Kyle Kappeler, and Qin M. Chen. "G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress." AMER SOC MICROBIOLOGY, 2017. http://hdl.handle.net/10150/622753.
Повний текст джерелаReznichenko, Oksana. "Combinatorial chemistry approaches for the development of G-quadruplex DNA and RNA ligands." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASF014.
Повний текст джерелаG-quadruplexes (G4s) are four-stranded structures of nucleic acids (DNA or RNA) that consist of at least two coplanar guanine quartets. An important feature of G4s is their ability to form stable complexes with exogenous small molecules (ligands) and thus influence biological processes in which they are involved. G4 targeting is often associated with oncology, where G4 ligands may suppress the expression of oncogenes, inhibit telomerase, or induce DNA damage in cancer cells. This work aims to develop methodologies for rapid and simple synthesis and screening of compounds, in order to identify selective and highly affine ligands of given non-canonical structures of nucleic acids, in particular G4s. Specifically, this works exploits the chemistry of reversible synthesis of acylhydrazones, which has been barely applied for the development of DNA or RNA ligands before. First, a small library of 20 cationic bis(acylhydrazones), analogues of the previously reported G4-ligands PDC (360A) and PhenDC3, was obtained by preparative synthesis. Through fluorescence melting experiments it is demonstrated that some of compounds indeed have high affinity to G4-DNA, validating the suitability of the acylhydrazone motif as a scaffold for the development of G4 ligands. Next, a method of dynamic combinatorial chemistry (DCC), which consists in simultaneous one-pot generation of libraries of up to 20 compounds with consecutive pull-down of most affine ligands by bead-immobilized targets (i.e., G4-DNA), was developed. By using this method, a non-symmetrical bis(acylhydrazone) was identified as a promising ligand of a parallel G4-DNA Pu24T. However, biophysical experiments with its close structural analogues did not confirm their preferential binding in comparison with the symmetrically substituted compound. It is proposed that the outcome of DCC experiments may be biased by non-specific interactions of ligands with magnetic beads, leading to false-positive results. In order to improve the analysis of dynamic combinatorial libraries, a novel method based on solid-phase extraction of the G4-ligand complex was developed and applied to two libraries of non-symmetric acylhydrazones. In a few rounds of selection, 13 hits were obtained out of 70 in situ generated compounds. Three of them were selected for preparative synthesis and detailed study of interaction with G4-DNA. In parallel, a classical combinatorial chemistry approach was developed, resulting in generation of a combinatorial library of 90 individual bis(acylhydrazone) derivatives in the form of ready-to-use 2 mM solutions in DMSO, with an average purity of 87%. These samples were directly used for biophysical screening experiments towards four G4-DNA targets of three different topologies. Three most active compounds were obtained in preparative manner and their interaction with the mentioned biological targets was studied in detail by several biophysical methods, including native mass spectrometry experiments. This way, at least one derivative with a G4-DNA affinity superior to that of PhenDC3 and unprecedented selectivity towards anti-parallel G4-DNA could be identified. Finally, in the framework of a collaborative project (M. Blondel, University of Western Brittany) the ligands synthesized in this work were studied with respect to their capacity to act as modulators of the immune evasion of Epstein–Barr virus (EBV). Specifically, it was shown that several bis(acylhydrazones) bind in vitro to G4-RNA structures formed by the guanine-rich repeat sequence of mRNA encoding for the glycine-alanine rich (GAr) domain of viral genome maintenance protein EBNA1. Moreover, two derivatives were found to displace the host cell factor nucleolin from EBNA1 mRNA, leading to overexpression of EBNA1 protein and a concomitant increase of antigen presentation in EBV-infected cell cultures. This effect represents an interesting therapeutic opportunity for treatment of EBV-related cancers
McLoughlin, David J. "Analysis of the ligand binding site of the human 5-HTâ†1â†A serotonin receptor." Thesis, University of Kent, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285980.
Повний текст джерелаAl-Furoukh, Natalie [Verfasser], Thomas [Akademischer Betreuer] Braun, and Robert [Akademischer Betreuer] Tampé. "Characterization of mouse NOA1: subcellular localizaion, G-Quadruplex binding and proteolysis / Natalie Al-Furoukh. Gutachter: Thomas Braun ; Robert Tampé." Frankfurt am Main : Univ.-Bibliothek Frankfurt am Main, 2014. http://d-nb.info/1053704224/34.
Повний текст джерелаShrestha, Mahesh K. "Generation of chimeric receptors (GPR40/41) to identify domains responsible for ligand binding and insulin secretion." Virtual Press, 2008. http://liblink.bsu.edu/uhtbin/catkey/1409587.
Повний текст джерелаDepartment of Biology
Zaidi, Saheem. "Understanding ligand binding, selectivity and functions on the G protein-coupled receptors: A molecular modeling approach." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/596.
Повний текст джерелаLee, Katarina. "Binding and Cellular Processing a Fluorescent G-Protein Coupled Receptor Ligand Cy5-Melanocyte Stimulating Hormone (cy5-MSH)." Thesis, The University of Arizona, 2014. http://hdl.handle.net/10150/321790.
Повний текст джерелаBoukharta, Lars. "Computational Modelling of Ligand Complexes with G-Protein Coupled Receptors, Ion Channels and Enzymes." Doctoral thesis, Uppsala universitet, Beräknings- och systembiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-212103.
Повний текст джерелаEngelhard, David Maximilian [Verfasser], Guido [Akademischer Betreuer] [Gutachter] Clever, and Claudia [Gutachter] Höbartner. "Synthesis and coordination chemistry of tetradentate chelators based on ligand-appended G-quadruplex structures / David Maximilian Engelhard ; Gutachter: Guido Clever, Claudia Höbartner ; Betreuer: Guido Clever." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1121909876/34.
Повний текст джерелаBeauvarlet, Jennifer. "Caractérisation du rôle de la voie de réponse aux dommages à l'ADN et des lysosomes dans la mort cellulaire et la sénescence induites par un ligand G-quadruplexe." Thesis, Bordeaux, 2018. http://www.theses.fr/2018BORD0318.
Повний текст джерелаG-quadruplexes (G4) are unusual nucleic acid structures that can be formed by guanine-rich DNA and RNA. Through their ability to stabilize G4 structures, G4 ligands (G4L) have been described to display potent anticancer properties. Here, we studied the G4L 20A belonging to the triarylpyridine family of compounds that have the ability to efficiently bind to and stabilize G4 structures in vitro. The objectives of this work were to determine the molecular and cellular mechanisms responsible for the anti-proliferative effects of 20A in cancer cells. In this study, we showed that 20A causes cancer cell growth arrest in cell culture and a mice tumour xenograft model, through induction of senescence and apoptotic cell death. These cellular responses are associated with the induction of the DNA damage response pathway (DDR), in particular ATM activation, which promotes the induction of both autophagy (a lysosomal catabolic pathway) and senescence, while protecting cells against apoptosis. Furthermore, we found that 20A induces failure of cytokinesis which results in the accumulation of binucleated cells that display marked resistance to 20A-induced cell death. Unexpectedly, we found that 20A accumulates in the lysosomal compartment and causes lysosome enlargement. The combination of a lysosomotropic agent, chloroquine, and 20A promotes a significant induction of lysosomal membrane permeabilization (LMP) and a robust cell death. In particular, this combination significantly sensitizes binucleated cells to cell death. Altogether, our results uncover the relationship of the DDR and lysosomal pathways to cell death and senescence induced by the G4L 20A. Such regulation should also be taken into account when using antiproliferative drugs susceptible to interfere with the lysosomal functions
Liu, Fang. "Direct binding of dopamine D5 with GABA¦A receptors enables ligand gated and G-protein coupled receptor cross-talk." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0007/NQ41214.pdf.
Повний текст джерелаLe, Bras Morgane. "Rôle des protéines de liaison à l'ARN hnRNP H et hnRNP F dans les régulations traductionnelles dans les glioblastomes." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30277.
Повний текст джерелаGlioblastoma multiforme (GBM) is one of the most aggressive brain tumors with poor prognosis. Understanding the molecular mechanisms involved in the development and resistance to treatments of gliomas could improve treatment efficiency. Recently, it has been demonstrated that translational regulations play a key role in the GBM aggressivity. RNA binding proteins (RBP) are major regulators of these processes and have altered expression / activity in GBM. The RBP hnRNP H and hnRNP F (HF) are among the most overexpressed RBP in GBM and their role in GBM translational regulation has never been investigated yet. We hypothesize that HF are at the core of a post-transcriptional regulation network which impacts the translational machinery that controls GBM tumor development and resistance to treatment. We have demonstrated that hnRNP H and hnRNP F regulate proliferation and response to treatment because their depletion (i) decreases the GBM proliferation (cell line model, spheroid and in vivo xenografts), (ii) activates the DNA damage response pathways and (iii) sensitizes the GBM cells to irradiation. We have identified HF as new regulators of GBM translation. Indeed, our data show that hnRNP H and hnRNP F control mRNA translation by regulating expression/activity of initiation factors and in collaboration with RNA helicases by targeting mRNA involved in oncogenic processes and containing secondary structures called G-quadruplex in their 5'UTR. The data that we have generated suggest that HF are essential translational regulators involved in tumor development and resistance to treatment in GBM
Iwasiow, Rafal M. "Delineating the molecular basis of subtype-specific ligand binding, G protein coupling and signaling properties of D1 and D5 dopaminergic receptors." Thesis, University of Ottawa (Canada), 2004. http://hdl.handle.net/10393/29118.
Повний текст джерелаStefan, Loïc. "Template-Assembled Synthetic G-Quartets (TASQ) hydrosolubles : du ligand de quadruplexes d'ADN et d'ARN à la plateforme catalytique." Thesis, Dijon, 2013. http://www.theses.fr/2013DIJOS084/document.
Повний текст джерелаNatural G-quartets, a cyclic and coplanar array of four guanine residues held together via Hoogsteen H-bond network, have recently received much attention due to their involvement in G-quadruplex-DNA, an alternative higher-order DNA structure strongly suspected to play important roles in key cellular events (chromosomal stability, regulation of gene expression). Besides this, synthetic G-quartets, which artificially mimic native G-quartets, have also been widely studied for their involvement in nanotechnological applications (i.e. nanowires, artificial ion channels, etc.). In contrast, intramolecular synthetic G-quartets, also named template-assembled synthetic G-quartet (TASQ), have been more sparingly investigated, despite a technological potential just as interesting.In this way, we designed and synthesized three series of innovative hydrosoluble TASQ: DOTASQ (for DOTA-Templated Synthetic G-Quartet), PorphySQ (containing a porphyrin template) and the most effective PNADOTASQ where PNA-guanine arms replace native DOTASQ alkyl-guanine arms. We report herein the results of both DNA and RNA interactions (notably their selective recognition of quadruplex-DNA according to a bioinspired process) and peroxidase-like hemin-mediated catalytic activities (either in an autonomous fashion as precatalysts for TASQzyme reactions, or in conjunction with quadruplex-DNA as enhancing agents for DNAzyme processes). These results provide a solid scientific basis for TASQ to be used as multitasking tools for bionanotechnological applications
Ullmann, R. Thomas [Verfasser], and G. Matthias [Akademischer Betreuer] Ullmann. "Monte Carlo Simulation Methods for Studying the Thermodynamics of Ligand Binding & Transfer Processes in Biomolecules / R. Thomas Ullmann. Betreuer: G. Matthias Ullmann." Bayreuth : Universität Bayreuth, 2012. http://d-nb.info/1059469634/34.
Повний текст джерелаDesuzinges-Mandon, Elodie. "Rôle du domaine extracellulaire d’ABCG2 dans l’homéostasie des porphyrines." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10236/document.
Повний текст джерелаABCG2 belongs to the ABC-transporter family, involved in drug resistance developed by cells, notably cancer cells. This transporter has also a physiological role of endobiotic detoxification, in particular porphyrins that are essential but potentially toxic molecules. This toxicity implies a specific handle, to avoid them to remain free in solution. In that context, we hypothesized that ABCG2 participate to this detoxification, limiting the intracellular porphyrin accumulation by presenting them to an extracellular partner. We show that ABCG2 transports heme and some of its derivatives and precursors. Interestingly, these porphyrins, unlike other ABCG2 (non-porphyric) substrates, can bind to an extracellular domain, specific of ABCG2, ECL3, 70 residues-long. ECL3 displays affinities for porphyrins in the range of 0.5 to 3.5 μM, high enough to allow their binding after transport. We also show that human serum albumin, implicated in heme detoxification, releases porphyrins bound to ECL3 by a direct interaction with ABCG2. This work established a better comprehension of ABCG2 role in porphyrin and in particular heme homeostasis regulation. In addition, our results contribute to elucidate part of the molecular mechanism by which such regulation is carried out
Shabajee, Preety. "Contribution a l'identification des ligands endogènes de deux récepteurs couplés aux protéines G d'intérêt thérapeutique et d'un site de liaison à la mélatonine. MTx, a new melatonin binding site in sheep brain : discovery, characterization and molecular pharmacology." Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR131.
Повний текст джерелаG-protein coupled receptors (GPCR) are the largest transmembrane protein family of the genome.Although, they are involved in numerous physiological processes, there are still some receptors among this family for which no ligand has been identified yet. These are called orphan receptors. We focused on two of these orphan receptors: GPR88 and GPR21, showing therapeutic potential in schizophrenia and diabetes mellitus, respectively. During this PhD thesis, we aimed to identify the ligands of these receptors using functional assays and by screening endogenous compounds libraries. Our approaches allowed us to identify the cerebro-spinal fluid (CSF) as a source for the GPR88 receptor ligand. This molecule appears to be very polar with a molecular weight below 3kDa . We also ruled out some compounds contained in the CSF, that we identified in active fractions by mass spectrometry. Concerning GPR21, the assays developped in our laboratory did not permit to detect any specific activity in the libraries nor in the tested biological fluids. In a second part of this PhD program, we pharmacologically characterized a new melatonin (MLT) binding site, named MTx. This site was discovered through autoradiography experiments, with high radiolabelled doses of MLT. MLT is a hormone, mainly synthesized at night by the pineal gland. It is involved in numerous physiological processes and in regulating circadian and circannual rhythms. The identification of this new site, as well as deciphering its roles, might allow us to enrich our knowledge on MLT, and to understand the mode of action of some treatments involving melatoninergic compounds. This site has a pharmacological profile unprecedently described. It can bind both MLT and serotonin, which is not the case with classical melatoninergic nor serotoninergic receptors. Our objectives for the work on MTx, was to identify the gene/protein responsible for the MLT binding and subsequently perform functional studies to further characterize this protein
Mandon, Elodie. "Rôle du domaine extracellulaire d'ABCG2 dans l'homéostasie des porphyrines." Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00868903.
Повний текст джерелаKlenowski, Paul Mark. "Molecular and structural requirements of the ß1L-adrenoceptor." Thesis, Queensland University of Technology, 2012.
Знайти повний текст джерелаBarwich, Ann-Sophie. "Making sense of smell : classifications and model thinking in olfaction theory." Thesis, University of Exeter, 2013. http://hdl.handle.net/10871/13869.
Повний текст джерелаLópez, Muñoz Laura. "Homology modeling and structural analysis of the antipsychotic drugs receptorome." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/7228.
Повний текст джерелаThe study started with obtaining homology models for all the receptors putatively involved in the antipsychotic drugs receptorome, suitable for building consistent drug-receptor complexes. These complexes were structurally analyzed and compared using multivariate statistical methods, which in turn allowed the identification of the relationship between the pharmacological properties of the antipsychotic drugs and the structural differences in the receptor targets. The results can be exploited for the design of safer and more effective antipsychotic drugs with an optimum binding profile.
Tradicionalmente se asumía que los fármacos terapéuticamente efectivos actuaban interaccionando con un único receptor. Actualmente está ampliamente reconocido que el efecto farmacológico de la mayoría de los fármacos es más complejo y abarca a un conjunto de receptores, algunos asociados a los efectos terapéuticos y otros a los secundarios y toxicidad. Los fármacos antipsicóticos son un ejemplo de compuestos eficaces que se caracterizan por unirse a varios receptores simultáneamente (principalmente a receptores unidos a proteína G, GPCR). El trabajo de la presente tesis se ha centrado en el estudio de los mecanismos moleculares que determinan el perfil de afinidad de unión por múltiples receptores de los fármacos antipsicóticos.
En primer lugar se construyeron modelos de homología para todos los receptores potencialmente implicados en la actividad farmacológica de dichos fármacos, usando una metodología adecuada para construir complejos fármaco-receptor consistentes. La estructura de estos complejos fue analizada y se llevó a cabo una comparación mediante métodos estadísticos multivariantes, que permitió la identificación de asociaciones entre la actividad farmacológica de los fármacos antipsicóticos y diferencias estructurales de los receptores diana. Los resultados obtenidos tienen interés para ser explotados en el diseño de fármacos antipsicóticos con un perfil farmacológico óptimo, más seguros y eficaces.
Paul, Ananya. "Benzimidazole Based Novel Ligands For Specific Recognition Of Duplex And G-Quadruplex DNA." Thesis, 2011. http://etd.iisc.ernet.in/handle/2005/2119.
Повний текст джерелаTseng, Ting-Yuan, and 曾鼎元. "Investigation of ligand binding sites and structural analysis of G-quadruplexes by using fluorescence decays of BMVC-2 in DNA gels." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/91741098295212587308.
Повний текст джерела國立陽明大學
生醫光電工程研究所
96
Telomeres, which are found in the end of chromosomes, and many gene promoters have guanine(G)-rich sequences. The length of telomeres can be maintained by telomerase to prevent cells from senescence, and their activities are revealed in more than 80% of all cancer cases. Gene promoters such as bcl-2 and vegf are related to the regulation of gene expression, and over-expressions of them are reported in many cancer studies. Interestingly, because telomeres and gene promoters are G-rich sequences, they are able to form the G-quadruplex structures. It is important to investigate the various G-quadruplex structures formed by the original and modified telomeric and non-telomeric sequences. In our experiment, we use the new fluorescent probe 3,6-bis (1-methyl-2-vinylpyridinium)carbazole diiodide (BMVC-2) as the binding ligand, and combine polyacrylamide electrophoresis and fluorescence lifetime image microscopy to measure the ligand-binding signals in order to study the G-quadruplex structures. From the analysis of fluorescence decay curves, we can deduce that G-quadruplex structures have mainly two ligand-binding modes. One is terminal stacking and the other is non-specific binding. Furthermore, when the loop sequences of the G-quadruplexes are reduced to single nucleotide, the π-π interaction of terminal stacking will be effected, leading to the change in fluorescence decay time of BMVC-2. On the other hand, when we modify the loop sequences without effecting the π-π interaction of terminal stacking, the change in fluorescence decay time of BMVC-2 is less. To our knowledge, this is the first time that the loop effect on the π-π interaction of terminal binding ligand to the G-quadruplexes has been evaluated.
(8740836), Guanhui Wu. "Protein and Ligand Interactions of MYC Promoter G-quadruplex." Thesis, 2020.
Знайти повний текст джерелаSilva, João Medeiros. "G-quadruplex ligands for cancer therapy." Master's thesis, 2015. http://hdl.handle.net/10362/15840.
Повний текст джерелаBack, Hong-Tsun, and 白康俊. "The anti-cancer effect of BMVC, a G-quadruplex binding compound." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/38963254593377698397.
Повний текст джерела國立臺灣大學
口腔生物科學研究所
93
Compare to normal somatic cells, more than 85% of cancer cells have higher telomerase activity to maintain their length of telomere. Therefore, inhibiting the function of telomerase is a considerable way to interfere cancer proliferation. BMVC was designed for interacting with G-quadruplex, a DNA four strand structure that is abounded with Guanine nucleotides, especially the sequence of human telomere [5’-(TTAGGG)n-3’]. Based on acute cytotoxicity assay, BMVC has higher cytotoxicity on cancer cells, which 50% lethal dose is about 10 μM. According to telomeric repeat amplification protocol assay, BMVC is a potent telomerase inhibitor with 50% inhibition concentration at 0.25 μM. Under confocal microscopy observation, BMVC enter the nucleus which might further affect cellular function. Cell culture and animal study show that proliferation ability of cancer cells may inhibited under nonacute cytotoxic concentration of BMVC treatment.
Kern, Jonathan Thurston. "Studies on 3,4,9,10-perylenetetracarboxylic acid diimide based ligands as G-quadruplex DNA interactive agents." Thesis, 2002. http://wwwlib.umi.com/cr/utexas/fullcit?p3110629.
Повний текст джерелаMcKee, Mireya Loreley 1978. "Synthesis and biological evaluation of 2-(2'-hydroxyphenyl) benzoxazole analogs of UK-1 and G-quadruplex selectivity of perylene diimide compounds: /." Thesis, 2007. http://hdl.handle.net/2152/3634.
Повний текст джерелаChen, Chien-Han, and 陳建漢. "Development of Credible Molecular Probes to Identify Pregnenolone-Binding Proteins and Site-Selectively Alkylate G-Quadruplex DNA." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/86330457034233765253.
Повний текст джерела國立臺灣大學
化學研究所
104
The work presented here consists of two parts: Section I describes that pregnenolone (P5) was equipped with benzophenone photoreactive group and biotin tag at C7 position in ether linkage to explore P5-binding proteins in the stage of embryonic development of the zebrafish. Various spacer lengths and orientations of P5-photoaffinity probes had been employed to investigate the influences on the activity of in vitro tubulin polymerization. With the preservation of the biological functions as P5, P5-NBPN was used to label P5-binding proteins from zebrafish embryo lysates and the P5 binding protein (Figure 1), cytoplasmic linker protein 170 (CLIP-170), had ultimately been found by LC-MS/MS identification. The photolabeling experiments of CLIP-170 and/or its various depletion mutants showed that the binding region of P5 on CLIP-170 located in the region between aa 920-970 with remarkable labeling selectivity and specificity. Section II describes that a series of G-quadruplex (G-4)-directing alkylating agents, BMVC-CnM (n = 2, 3, and 6) and BMVC-SW, integrating BMVC with aniline mustard in spacers of various lengths or with longer bridge length to react with different G-4 structures (hybrid-2 type, antiparallel and parallel) (Figure 2). The intact alkylated adducts were elaborately characterized by electrospray ionization mass spectroscopy (ESI-MS), LC-MS, and chemical/enzymatic footprinting to determine precise alkylation sites and plausible binding profiles. These results indicated that alkylation selectivity, specificity, and reactivity are modulated by adjusting linker lengths, whereas intrastrand cross-link efficiency which showed higher cytotoxicity is determined by the distance between two reactive warheads. Our preliminary findings regarding the different distance effects on G-4-specific alkylation provide a structural foundation for the development of G-4-selective bifunctional alkylating agents.
"Effects of the adenosine A2A receptor C-terminus on ligand binding, stability, and downstream signaling." Tulane University, 2019.
Знайти повний текст джерелаG protein-coupled receptors (GPCRs) are the largest family of proteins in humans and are expressed widely throughout the body. GPCRs consist of seven-transmembrane helices that bind extracellular ligands to initiate intracellular downstream signaling via interaction with G proteins, and function in many short and long-term responses in the body, including taste, immune function, and sugar sensing. Extracellular binding and the coupled downstream signaling pathway means that GPCRs are ideal drug targets for many diseases, making them of great interest to the pharmaceutical industry. Some GPCRs have been crystallized in an effort to better elucidate the structure-function relationship to aid in the design of novel therapeutics. The adenosine A2A receptor (A2AR) is a GPCR that has been crystallized bound to agonist, antagonist, and G protein. Although these crystal structures are informative in regards to A2AR structure when associated with binding partners, all current crystal structures truncate nearly 100 amino acids of the C-terminus. As a crystallization strategy, this truncation makes sense considering the C-terminus is long and unstructured. However, truncating roughly 25% of the protein, as well as making other point mutations calls into question the authenticity of the crystal structures in reflecting functional receptor and thus their potential value for therapeutic design. Beyond structural studies, biophysical characterization of drug binding to receptors in vitro to predict efficacy in vivo has shifted away from measures of affinity and selectivity and towards determination of kinetic rates. Kinetic rate constants in combination with affinity and drug residence time are thought to be better predictors of drug behavior in vivo. For these reasons, this thesis focuses on experiments to characterize A2AR kinetic rate constants. Previously, our lab showed that truncating the A2AR C-terminus reduced downstream cAMP signaling in mammalian cells, although where the effect on the signaling pathway occurred was not determined. Here, we report that truncation of the C-terminus ablates receptor association to Gαs, the first step in signaling. In this work, A2AR ligand binding kinetics, stability, and association to Gαs are characterized to better delineate the importance of interactions between receptor and stimuli in a way that is impactful to drug design.
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Kirsten Swonger Koretz
Evans, Timothy Lee. "Activity Analysis of the Fragile X Mental Retardation Protein Isoforms 1, 2 and 3: Recombinant Bacterial Expression and Purification with Subsequent Quantitative Analysis of Binding to in vivo Target G quadruplex Forming Ribonucleaic Acids and Regulation of Translation." 2010. http://digital.library.duq.edu/u?/etd,154374.
Повний текст джерелаBayer School of Natural and Environmental Sciences
Chemistry and Biochemistry;
PhD;
Dissertation;