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Structural basis of transcription inhibition by the nucleoside-analog inhibitor thuringiensin

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TitleInfo
Title
Structural basis of transcription inhibition by the nucleoside-analog inhibitor thuringiensin
Name (type = personal)
NamePart (type = family)
Yin
NamePart (type = given)
Ruiheng
DisplayForm
Ruiheng Yin
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Ebright
NamePart (type = given)
Richard
DisplayForm
Richard Ebright
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Arnold
NamePart (type = given)
Eddy
DisplayForm
Eddy Arnold
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Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Olson
NamePart (type = given)
Wilma
DisplayForm
Wilma Olson
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2016
DateOther (qualifier = exact); (type = degree)
2016-05
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2016
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Thuringiensin (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.
Subject (authority = RUETD)
Topic
Biochemistry
Subject (authority = ETD-LCSH)
Topic
Antibacterial agents
Subject (authority = ETD-LCSH)
Topic
Nucleosides
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_7123
PhysicalDescription
Form (authority = gmd)
electronic resource
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application/pdf
InternetMediaType
text/xml
Extent
1 online resource (vii, 36 p. : ill.)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Ruiheng Yin
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3S75JHW
Genre (authority = ExL-Esploro)
ETD graduate
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Yin
GivenName
Ruiheng
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-04-06 13:50:10
AssociatedEntity
Name
Ruiheng Yin
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2016-05-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2017-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2017.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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ETD
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windows xp
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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2016-04-08T15:31:59
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2016-04-08T15:31:59
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