Computational studies on interaction between some receptors and ligands of transforming growth factor -beta superfamily: Design of inhibitor(s) to promote osteogenesis
Item
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Title
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Computational studies on interaction between some receptors and ligands of transforming growth factor -beta superfamily: Design of inhibitor(s) to promote osteogenesis
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Identifier
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d_2009_2013:7b3e0414baf1:10333
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identifier
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10417
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Creator
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Ahmed, Shaila,
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Contributor
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Boojala Vijay B. Reddy
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Date
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2010
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Bioinformatics
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Abstract
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Transforming growth factor beta (TGF-beta) superfamily members execute distinct and intricate roles in numerous biological events such as cell growth, differentiation, embryogenesis, immune responses, and morphogenesis etc. Diverse cellular responses are instigated by binding of these superfamily members to specific transmembrane serine/threonine kinase receptors on the cell surface and thereby activating specific pathways. As a result receptor-regulated Smad proteins are phosphorylated, followed by their complex formation with Co-Smad that together translocates into nucleus and leads to the initiation of transcription of target genes. Bone morphogenic proteins (BMPs), activins, Inhibins are the most important members of TGF-beta family. When they exert their biological activity, they are sternly regulated by extracellular antagonists such as noggin, follistatin, CV2, and so forth that are expressed in close temporal and spatial proximity. Blocking these antagonists' interaction with their target receptor proteins helps to promote their respective biological responses when needed. This work is an attempt to use the current understanding of some of the receptors and ligands of TGF-beta superfamily members, namely BMPs, activins and inhibins and their antagonists such as noggin, follistatin, and crossveinless 2 (CV2) interactions through the analysis of their available complex structures to design small molecular inhibitors with an ultimate goal of promoting their respective biological responses.;Noggin is a major natural extracellular antagonist to BMPs which binds to BMPs and blocks binding of them to BMP-specific receptors and thus negatively regulates BMP-induced osteoblastic differentiation. BMPs signal through heteromeric protein complexes composed of type I and type II serine/threonine kinase receptors. Preventing the BMP-2/noggin interaction will preserve free BMP-2 and enhance the efficacy of BMP-2 to induce bone formation. One part of this work is an attempt to use the current understanding of BMP-2, and its interaction with its receptors and antagonists, through the analysis of known structures in protein data bank (PDB), to design inhibitors of BMP-2/noggin interaction with the goal of lowering the dose of BMP-2 required in clinical applications to promote osteogenesis.;Another TGF-beta superfamily member, the activin, exerts pivotal roles in male and female reproduction, and has powerful actions in growth and differentiation in various tissues. The ability of activins to assemble their receptor complex, however, is regulated by a number of extracellular binding proteins. Follistatin is one of the main inhibitors among them. Follistatin acts primarily by binding to activin and preventing its interaction with its receptor there by bio-neutralizes activin-mediated responses. Here our main hypothesis is to understand the activin interaction with its receptors and antagonist follistatin, through the available structures in PDB, to design small molecular binder that blocks activin/follistatin interaction with the goal of promoting BMP responsiveness of the cells.;Crossveinless 2 (CV2), a member of Chordin family, is an extracellular modulator of BMPs which has a unique feature of having both the anti- and pro-BMP activity depending on the cellular context. The anti-BMP activity is directed by excessive dosage of CV2 that impedes the BMP-dependent differentiation of osteoblast and chondrocyte in cell culture and in certain developmental stages. Crystal Structure of BMP-2/CV2-VWC1 domain is available. Here, our main goal is to design a potential inhibitor of BMP-2/CV2 interaction to promote osteoblast differentiation leading to promotion of bone healing. We analyzed the available complex structures to identify contact region of CV2 with BMP-2. By using the binding information of BMP with its receptors from BMP-2/noggin studies, we performed virtual screening and identified several compounds that are likely to bind to CV2 and block BMP-2/CV2 interaction that may enhance the ectopic bone formation.;Finally, by using the BMP-2 sequence fragments that are in contact with noggin, from the BMP/noggin complex structure, we designed several, di-, tri- and tetra-peptide combination structures and docked them onto respective binding sites on noggin with future goal to develop modified peptide mimetic compounds that may help blocking BMP/noggin binding to promote osteogenesis.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
