Browsing by Subject "protein"

Now showing 1 - 4 of 4
  • No Thumbnail Available
    Item
    Dehydron as a Marker For Drug Design
    (2006-07-26T14:23:51Z) Jain, Manojkumar D.; Fernandez, Ariel
    The approach of exploiting highly conserved protein folds and structure in understanding protein function and in designing drugs leads to drugs that are less selective due to association with similar proteins. Over the years an open problem for researchers has been to develop drug design models based on non-conserved features to have higher selectivity. Recently a new structural feature, the dehydron, has been demonstrated to vary across proteins with conserved folds. Dehydrons are backbone hydrogen bonds that are not adequately protected from water. The importance of wrapping dehydrons in ligand binding and non-conservation of dehydrons across similar proteins makes them important candidates for markers in drug design. Investigation on a series of proteins – PDB entries: 1IA8, 1NVQ, 1NVS, 1NVR, 1OKZ, and 1PKD – revealed the potential impact of wrapping on binding affinity of the ligands. Unlike in 1NVS, 1NVR, 1OKZ, and 1PKD, inhibitor UCN in 1NVQ wrapped both the dehydrons in active site region of the checkpoint protein kinase, thereby indicating an increased potency and higher selectivity. On detailed analysis of 193 protein kinases, roughly 70% were found to have two or more dehydrons in the neighborhood of the bound ligand. Also, about 70% of proteins had dehydrons within the active site region. Only around 20% of ligands, however, actually wrapped two or more dehydrons. These statistics clearly illustrate the significance of dehydrons and their potential use as markers for drug design to enhance drug efficacy as well as selectivity, and to reduce side effects in the process.
  • Thumbnail Image
    Item
    EFFECT OF TOBACCO-TREATED MG63 OSTEOBLAST ON HUMAN PULP CELLS
    (Office of the Vice Chancellor for Research, 2012-04-13) Gebreslassie, Seret; Huang, Ruijie; Li, Mingyun; Song, Fengeyu; Gregory, Richard L.
    Objective: The objective of this study is to determine the effects of to-bacco products on protein concentration and growth of MG63 osteoblasts and the effects of the bacterial cells and culture supernatants on human pulp cells. The study was designed to observe the effects of P.gingivalis grown in four different tobacco solutions such as CSC (cigarette smoked condensate), nicotine (chewing tobacco), and DST (dissolvable smokeless tobacco) strips, and in the media control only without tobacco products. Methods: MG63 os-teoblast was grown in BHI-YE (Bacteria Heart Infusion-Yeast Extract) and hemin-vitamin K. In addition, MG63 osteoblast was grown in BHI-Y-E con-taining nicotine, CSC, and DST. Human pulp cells were grown in media con-taining BGS (Bovine Growth Serum) and washed. The pulp cell cultures will be assayed for cytotoxicity and the supernatants will be assayed for cyto-kines and MMP expression. Results: The protein assays was performed us-ing a microplate spectrophometer and SoftMax Pro 5.2, and we observed that nicotine and DST treated cells had significantly less protein than control cells, however, CSC treated cells had significantly more protein. The undilut-ed control had significantly less protein than the tobacco-treated superna-tants. Conclusion: Based on the previous experiments, we speculate that the additional protein in the undiluted CSC cells and tobacco-treated super-natant may stimulate more effect on human pulp cells than the control, nico-tine or DST treated cells or the control supernatant.
  • Thumbnail Image
    Item
    Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy
    (Nature Publishing Group, 2015-06-16) Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.; Farlow, Martin R.; Grafman, Jordan; Huey, Edward D.; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T.; Kretzschmar, Hans A.; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L.; Vonsattel, Jean Paul G.; Van Deerlin, Vivianna M.; Grossman, Murray; Hurtig, Howard I.; Gross, Rachel G.; Arnold, Steven E.; Trojanowski, John Q.; Lee, Virginia M.; Wenning, Gregor K.; White, Charles L.; Höglinger, Günter U.; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I.; Crook, Julia; Parisi, Joseph E.; Boeve, Bradley F.; Josephs, Keith A.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Graff-Radford, Neill R.; Litvan, Irene; Younkin, Steven G.; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D.; Dickson, Dennis W.; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
  • Thumbnail Image
    Item
    Phosphorylation State-Dependent Regulation of SAPAP3 and mGluR5 Association
    (Office of the Vice Chancellor for Research, 2015-04-17) Morris, Cameron; Baucum, A.J.; Edler, Mike
    This study aims to characterize the interaction between SAP90/PSD-95-associated protein 3 (SAPAP3) and metabotropic Glutamate Receptor 5 (mGluR5); specifically focusing on how SAPAP3 phosphorylation state modulates association. SAPAP3 is a scaffolding protein localized to the postsynaptic density (PSD) of striatal neurons and SAPAP3 knockout mice have Obsessive-Compulsive Disorder-like symptoms. Here, we hypothesize that spinophilin modulates SAPAP3 phosphorylation and alterations in SAPAP3 phosphorylation regulate SAPAP3 binding to mGluR5. We will use in vitro and ex vivo studies to characterize the interaction between spinophilin and SAPAP3 and to determine the functional implications of SAPAP3 phosphorylation on mGluR5 binding. These data will enhance our understanding of molecular mechanisms that regulate SAPAP3 and mGluR5 function, two proteins with known roles in obsessive-compulsive disorder.