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Template-assembled peptide models of the N-peptide helix bundle from HIV-1 Gp41

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TitleInfo (displayLabel = Citation Title); (type = uniform)
Title
Template-assembled peptide models of the N-peptide helix bundle from HIV-1 Gp41
Name (ID = NAME001); (type = personal)
NamePart (type = family)
Xu
NamePart (type = given)
Weiming
DisplayForm
Weiming Xu
Role
RoleTerm (authority = RULIB)
author
Name (ID = NAME002); (type = personal)
NamePart (type = family)
Taylor
NamePart (type = given)
John
Affiliation
Advisory Committee
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John W Taylor
Role
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chair
Name (ID = NAME003); (type = personal)
NamePart (type = family)
Romsted
NamePart (type = given)
Laurence
Affiliation
Advisory Committee
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Laurence Romsted
Role
RoleTerm (authority = RULIB)
internal member
Name (ID = NAME004); (type = personal)
NamePart (type = family)
Warmuth
NamePart (type = given)
Ralf
Affiliation
Advisory Committee
DisplayForm
Ralf Warmuth
Role
RoleTerm (authority = RULIB)
internal member
Name (ID = NAME005); (type = personal)
NamePart (type = family)
Lobel
NamePart (type = given)
Peter
Affiliation
Advisory Committee
DisplayForm
Peter Lobel
Role
RoleTerm (authority = RULIB)
outside member
Name (ID = NAME006); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (ID = NAME007); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2007
DateOther (qualifier = exact); (type = degree)
2007
Language
LanguageTerm
English
PhysicalDescription
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electronic
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application/pdf
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text/xml
Extent
xvii, 216 pages
Abstract
The HIV-1 pandemic is one of the most serious health problems facing the world today. Infection of target cells by HIV-1 is initiated by fusion of viral and cell membranes, which is mediated by the viral glycoproteins, gp120 and gp41. After initial cell binding by gp120, the folding of gp41 to form a stable six-helix bundle structure is directly associated with membrane fusion. This helix bundle is composed of an α-helical trimer of gp41 N-helices, with three copies of the α-helical gp41 C-peptides folded onto it in an antiparallel orientation. Peptides that interfere with the formation of this six-helix bundle structure by targeting either the N-helix or the C-helix are believed to be able to block the cell fusion process and therefore prevent HIV-1 infection.
In this study, we successfully synthesized three-helix peptide structures of gp41 as models of the internal N-helix bundle, by assembling three copies of N-peptides onto three-fold symmetric templates. The templates were derived from cis,cis-1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid (Kemp's Triacid, KTA) or tris(2-aminoethyl)amine (TREN), which represent choices of rigid and flexible molecules, respectively, for organization of the folding of the N-peptide three-helix bundle.
Biophysical analysis of the four synthetic model structures, KTA-3N29, TREN-3N29, KTA-3N29b and TREN-3K-N29b, demonstrated that, at neutral pH, they all exist as monomers with high helix contents. Binding isotherms, measured by circular dichroism spectropolarimetry in the presence of physiological salt, indicated that KTA-3N29b binds three copies of the C-peptide native sequence, with a KD of about 260 nM, while TREN-3K-N29b binds to C-peptide with a KD in the low-micromolar range. Within the scope of this investigation, KTA-Br, the relatively more rigid template derived from KTA, was the best design for a template for the N-peptide bundle, since it generated the most helical, and most stable three-helix bundle structure with the highest binding affinity for C-peptides. These features of KTA-3N29b demonstrate that this templated three-helix bundle serves as a functional model for the native N-peptide structure that will allow detailed studies of the folding and thermodynamic stability of the gp41 six-helix bundle, and may aid the future development of potent HIV-1 fusion inhibitors and immunogens.
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references.
Subject (ID = SUBJ1); (authority = RUETD)
Topic
Chemistry and Chemical Biology
Subject (ID = SUBJ2); (authority = ETD-LCSH)
Topic
Peptides
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.16799
Identifier
ETD_442
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/T3MS3T5X
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
AssociatedEntity (AUTHORITY = rulib); (ID = 1)
Name
Weiming Xu
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
RightsEvent (AUTHORITY = rulib); (ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
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License
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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.
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