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Inhibition of translation termination by small molecules targeting ribosomal release factors
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.ORCID iD: 0000-0001-7954-3195
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0003-3326-8495
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.ORCID iD: 0000-0002-6463-9116
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2019 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 15424Article in journal (Refereed) Published
Abstract [en]

The bacterial ribosome is an important drug target for antibiotics that can inhibit different stages of protein synthesis. Among the various classes of compounds that impair translation there are, however, no known small-molecule inhibitors that specifically target ribosomal release factors (RFs). The class I RFs are essential for correct termination of translation and they differ considerably between bacteria and eukaryotes, making them potential targets for inhibiting bacterial protein synthesis. We carried out virtual screening of a large compound library against 3D structures of free and ribosome-bound RFs in order to search for small molecules that could potentially inhibit termination by binding to the RFs. Here, we report identification of two such compounds which are found both to bind free RFs in solution and to inhibit peptide release on the ribosome, without affecting peptide bond formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 9, article id 15424
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Medicinal Chemistry Structural Biology
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URN: urn:nbn:se:uu:diva-396310DOI: 10.1038/s41598-019-51977-1ISI: 000492832300009PubMedID: 31659219OAI: oai:DiVA.org:uu-396310DiVA, id: diva2:1367284
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish National Infrastructure for Computing (SNIC)Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2022-09-15Bibliographically approved

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Ge, XueliangOliveira, AnaHjort, KarinBergfors, TereseGutiérrez-de-Terán, HugoAndersson, Dan ISanyal, SuparnaÅqvist, Johan

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Ge, XueliangOliveira, AnaHjort, KarinBergfors, TereseGutiérrez-de-Terán, HugoAndersson, Dan ISanyal, SuparnaÅqvist, Johan
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Molecular BiologyComputational Biology and BioinformaticsDepartment of Medical Biochemistry and MicrobiologyStructural Biology
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