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Search: WFRF:(Desroses Matthieu)

  • Result 11-13 of 13
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11.
  • Svensson, Linda M., et al. (author)
  • Crystal structure of human MTH1 and the 8-oxo-dGMP product complex
  • 2011
  • In: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 585:16, s. 2617-2621
  • Journal article (peer-reviewed)abstract
    • MTH1 hydrolyzes oxidized nucleotide triphosphates, thereby preventing them from being incorporated into DNA. We here present the structures of human MTH1 (1.9 angstrom) and its complex with the product 8-oxo-dGMP (1.8 angstrom). Unexpectedly MTH1 binds the nucleotide in the anti conformation with no direct interaction between the 8-oxo group and the protein. We suggest that the specificity depends on the stabilization of an enol tautomer of the 8-oxo form of dGTP. The binding of the product induces no major structural changes. The structures reveal the mode of nucleotide binding in MTH1 and provide the structural basis for inhibitor design.
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12.
  • Zhang, Si Min, et al. (author)
  • Development of a chemical probe against NUDT15
  • 2020
  • In: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 16:10, s. 1120-1128
  • Journal article (peer-reviewed)abstract
    • The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.
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13.
  • Zhang, Si Min, et al. (author)
  • NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir
  • 2021
  • In: Cell Chemical Biology. - : Elsevier BV. - 2451-9456 .- 2451-9448. ; 28:12, s. 1693-1702
  • Journal article (peer-reviewed)abstract
    • Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.
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  • Result 11-13 of 13
Type of publication
journal article (12)
other publication (1)
Type of content
peer-reviewed (12)
other academic/artistic (1)
Author/Editor
Desroses, Matthieu (13)
Helleday, Thomas (11)
Stenmark, Pål (9)
Scobie, Martin (8)
Jemth, Ann-Sofie (8)
Koolmeister, Tobias (7)
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Warpman Berglund, Ul ... (5)
Loseva, Olga (4)
Zhang, Si Min (4)
Llona-Minguez, Sabin (4)
Homan, Evert J. (4)
Gustafsson, Robert (3)
Wiita, Elisee (3)
Kalderen, Christina (3)
Bräutigam, Lars (3)
Hagenkort, Anna (3)
Page, Brent D. G. (3)
Valerie, Nicholas C. ... (3)
Throup, Adam (3)
Almlöf, Ingrid (3)
Rudd, Sean G. (3)
Wallner, Olov (3)
Rehling, Daniel (3)
Henriksson, Martin (2)
Odell, Luke R (2)
Artursson, Per (2)
Svensson, Richard (2)
Lundbäck, Thomas (2)
Knapp, Stefan (2)
Axelsson, Hanna (2)
Altun, Mikael (2)
Gad, Helge (2)
Martens, Ulf (2)
Häggblad, Maria (2)
Baranczewski, Pawel (2)
Svensson, Linda M. (2)
Pham, Therese (2)
Berglund, Ulrika War ... (2)
Vallin, Karl S. A. (2)
Sarno, Antonio (2)
Rasti, Azita (2)
Sanjiv, Kumar (2)
Pudelko, Linda (2)
Carreras-Puigvert, J ... (2)
Homan, Evert (2)
Carter, Megan (2)
Eshtad, Saeed (2)
Jacques, Sylvain A. (2)
Ghassemian, Artin (2)
Göttmann, Mona (2)
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University
Stockholm University (9)
Karolinska Institutet (9)
Uppsala University (7)
Lund University (4)
University of Gothenburg (1)
Royal Institute of Technology (1)
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Linköping University (1)
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Language
English (13)
Research subject (UKÄ/SCB)
Natural sciences (12)
Medical and Health Sciences (6)

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