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  1. Article ; Online: Benchmarking network algorithms for contextualizing genes of interest.

    Abby Hill / Scott Gleim / Florian Kiefer / Frederic Sigoillot / Joseph Loureiro / Jeremy Jenkins / Melody K Morris

    PLoS Computational Biology, Vol 15, Iss 12, p e

    2019  Volume 1007403

    Abstract: Computational approaches have shown promise in contextualizing genes of interest with known molecular interactions. In this work, we evaluate seventeen previously published algorithms based on characteristics of their output and their performance in ... ...

    Abstract Computational approaches have shown promise in contextualizing genes of interest with known molecular interactions. In this work, we evaluate seventeen previously published algorithms based on characteristics of their output and their performance in three tasks: cross validation, prediction of drug targets, and behavior with random input. Our work highlights strengths and weaknesses of each algorithm and results in a recommendation of algorithms best suited for performing different tasks.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance

    Martin Schröder / Martin Renatus / Xiaoyou Liang / Fabian Meili / Thomas Zoller / Sandrine Ferrand / Francois Gauter / Xiaoyan Li / Frederic Sigoillot / Scott Gleim / Therese-Marie Stachyra / Jason R. Thomas / Damien Begue / Maryam Khoshouei / Peggy Lefeuvre / Rita Andraos-Rey / BoYee Chung / Renate Ma / Benika Pinch /
    Andreas Hofmann / Markus Schirle / Niko Schmiedeberg / Patricia Imbach / Delphine Gorses / Keith Calkins / Beatrice Bauer-Probst / Magdalena Maschlej / Matt Niederst / Rob Maher / Martin Henault / John Alford / Erik Ahrne / Luca Tordella / Greg Hollingworth / Nicolas H. Thomä / Anna Vulpetti / Thomas Radimerski / Philipp Holzer / Seth Carbonneau / Claudio R. Thoma

    Nature Communications, Vol 15, Iss 1, Pp 1-

    2024  Volume 19

    Abstract: Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug ... ...

    Abstract Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.
    Keywords Science ; Q
    Subject code 571
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Site-directed mutations and the polymorphic variant Ala160Thr in the human thromboxane receptor uncover a structural role for transmembrane helix 4.

    Raja Chakraborty / Sai Prasad Pydi / Scott Gleim / Shyamala Dakshinamurti / John Hwa / Prashen Chelikani

    PLoS ONE, Vol 7, Iss 1, p e

    2012  Volume 29996

    Abstract: The human thromboxane A2 receptor (TP), belongs to the prostanoid subfamily of Class A GPCRs and mediates vasoconstriction and promotes thrombosis on binding to thromboxane (TXA2). In Class A GPCRs, transmembrane (TM) helix 4 appears to be a hot spot for ...

    Abstract The human thromboxane A2 receptor (TP), belongs to the prostanoid subfamily of Class A GPCRs and mediates vasoconstriction and promotes thrombosis on binding to thromboxane (TXA2). In Class A GPCRs, transmembrane (TM) helix 4 appears to be a hot spot for non-synonymous single nucleotide polymorphic (nsSNP) variants. Interestingly, A160T is a novel nsSNP variant with unknown structure and function. Additionally, within this helix in TP, Ala160(4.53) is highly conserved as is Gly164(4.57). Here we target Ala160(4.53) and Gly164(4.57) in the TP for detailed structure-function analysis. Amino acid replacements with smaller residues, A160S and G164A mutants, were tolerated, while bulkier beta-branched replacements, A160T and A160V showed a significant decrease in receptor expression (Bmax). The nsSNP variant A160T displayed significant agonist-independent activity (constitutive activity). Guided by molecular modeling, a series of compensatory mutations were made on TM3, in order to accommodate the bulkier replacements on TM4. The A160V/F115A double mutant showed a moderate increase in expression level compared to either A160V or F115A single mutants. Thermal activity assays showed decrease in receptor stability in the order, wild type>A160S>A160V>A160T>G164A, with G164A being the least stable. Our study reveals that Ala160(4.53) and Gly164(4.57) in the TP play critical structural roles in packing of TM3 and TM4 helices. Naturally occurring mutations in conjunction with site-directed replacements can serve as powerful tools in assessing the importance of regional helix-helix interactions.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Correction

    Scott Gleim / Jeremiah Stitham / Wai Ho Tang / Hong Li / Karen Douville / Prashen Chelikani / Jeffrey J. Rade / Kathleen A. Martin / John Hwa

    PLoS ONE, Vol 8, Iss

    Human Thromboxane A2 Receptor Genetic Variants: In Silico, In Vitro and “In Platelet” Analysis

    2013  Volume 7

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  5. Article ; Online: Human thromboxane A2 receptor genetic variants

    Scott Gleim / Jeremiah Stitham / Wai Ho Tang / Hong Li / Karen Douville / Prashen Chelikani / Jeffrey J Rade / Kathleen A Martin / John Hwa

    PLoS ONE, Vol 8, Iss 6, p e

    in silico, in vitro and "in platelet" analysis.

    2013  Volume 67314

    Abstract: Thromboxane and its receptor have emerged as key players in modulating vascular thrombotic events. Thus, a dysfunctional hTP genetic variant may protect against (hypoactivity) or promote (hyperactivity) vascular events, based upon its activity on ... ...

    Abstract Thromboxane and its receptor have emerged as key players in modulating vascular thrombotic events. Thus, a dysfunctional hTP genetic variant may protect against (hypoactivity) or promote (hyperactivity) vascular events, based upon its activity on platelets. After extensive in silico analysis, six hTP-α variants were selected (C(68)S, V(80)E, E(94)V, A(160)T, V(176)E, and V(217)I) for detailed biochemical studies based on structural proximity to key regions involved in receptor function and in silico predictions. Variant biochemical profiles ranged from severe instability (C(68)S) to normal (V(217)I), with most variants demonstrating functional alteration in binding, expression or activation (V(80)E, E(94)V, A(160)T, and V(176)E). In the absence of patient platelet samples, we developed and validated a novel megakaryocyte based system to evaluate human platelet function in the presence of detected dysfunctional genetic variants. Interestingly, variant V80E exhibited reduced platelet activation whereas A160T demonstrated platelet hyperactivity. This report provides the most comprehensive in silico, in vitro and "in platelet" evaluation of hTP variants to date and highlightscurrent inherent problems in evaluating genetic variants, with possible solutions. The study additionally provides clinical relevance to characterized dysfunctional hTP variants.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

  6. Article ; Online: Correction

    Scott Gleim / Jeremiah Stitham / Wai Ho Tang / Hong Li / Karen Douville / Prashen Chelikani / Jeffrey J. Rade / Kathleen A. Martin / John Hwa

    PLoS ONE, Vol 8, Iss

    Human Thromboxane A Receptor Genetic Variants: , and “In Platelet” Analysis.

    2013  Volume 7

    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

    More links

    Kategorien

    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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