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Structural basis of transcription inhibition by the nucleoside-analog inhibitor thuringiensin
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Yin, Ruiheng. Structural basis of transcription inhibition by the nucleoside-analog inhibitor thuringiensin. Retrieved from https://doi.org/doi:10.7282/T3S75JHW

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TitleStructural basis of transcription inhibition by the nucleoside-analog inhibitor thuringiensin
NameYin, Ruiheng (author); Ebright, Richard (chair); Arnold, Eddy (internal member); Olson, Wilma (internal member); Rutgers University; Graduate School - New Brunswick
Date Created2016
Other Date2016-05 (degree)
SubjectBiochemistry, Antibacterial agents, Nucleosides
Extent1 online resource (vii, 36 p. : ill.)
DescriptionThuringiensin (Thg), also known as β-exotoxin, is an adenosine-containing secondary metabolite produced by the soil bacterium Bacillus thuringiensis. Thg exerts broad spectrum bactericidal activity, insecticidal activity, and mammalian toxicity by inhibiting bacterial RNA polymerase (RNAP) and eukaryotic RNAP I, II, and III. Biochemical evidence indicates that Thg inhibits RNAP by functioning as a nucleoside-analog inhibitor (NAI) that competes with ATP for occupancy of the RNAP active center "i+1" nucleotide binding site. We have determined a crystal structure of a Thermus thermophilus initial transcribing complex in complex with Thg (RPo-GpA-Thg; resolution = 3.2 Å; Rfree = 25.4%). The structure shows that Thg occupies the RNAP active-center "i+1" nucleotide-binding site. The adenine and ribose moieties of Thg make the same interactions with a DNA template-strand thymine, the RNA 3' nucleotide base, and the RNAP "i+1" NTP binding site as are made by the adenine and ribose moieties of ATP. The phosphate, allaric acid, and glucose moieties of Thg make interactions that mimic interactions made by the triphosphate moiety of ATP. In particular, the phosphate moiety of Thg occupies essentially the same position as is occupied by the  phosphate of ATP, and the phosphate moiety and one carboxy group of the allaric acid moiety of Thg coordinate a Mg2+ ion (Mg2+ II) in essentially the same manner and same position as the -phosphate and -phosphate of ATP coordinate Mg2+ II. The structure shows conclusively that Thg inhibits RNAP by functioning as an NAI that competes with ATP for binding to the RNAP active center "i+1" nucleotide binding site. This structure of RNAP in complex with the non-selective NAI Thg is one of the first two structures of a bacterial RNAP in complex with an NAI. NAIs of viral nucleotide polymerases have been the subject of intense interest, and immense importance, for the development of anti-HIV and anti-HCV drugs. NAIs of bacterial RNAP only now are beginning to be explored, but show high promise for the development of antibacterial drugs. The structures of the RNAP-Thg complexes provide a starting point for structure-based understanding of bacterial-RNAP-selectivity of NAIs and for structure-based design of more potent bacterial-RNAP-selective NAIs.
NoteM.S.
NoteIncludes bibliographical references
Noteby Ruiheng Yin
Genretheses, ETD graduate
Persistent URLhttps://doi.org/doi:10.7282/T3S75JHW
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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