2011
DOI: 10.1073/pnas.1101414108
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Trimeric HIV-1 glycoprotein gp140 immunogens and native HIV-1 envelope glycoproteins display the same closed and open quaternary molecular architectures

Abstract: The initial step in HIV-1 infection occurs with the binding of cell surface CD4 to trimeric HIV-1 envelope glycoproteins (Env), a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120). The design of soluble versions of trimeric Env that display structural and functional properties similar to those observed on intact viruses is highly desirable from the viewpoint of designing immunogens that could be effective as vaccines against HIV/AIDS. Using cryoelectron tomography combined w… Show more

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Cited by 146 publications
(198 citation statements)
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“…Despite their definition as variable loops, the V2 and V3 regions of gp120 contain highly conserved domains (33). Because several lines of evidence suggest that V3 establishes direct interaction with V2 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and the conserved base of V3 is the binding site for the N-terminal region of the CCR5 coreceptor (34), we looked for potential structural homology between V2 and CCR5. We recognized that the conserved central region of V2 contains two tyrosine residues (Tyr173 and Tyr177) with spacing identical to that of two tyrosines (Tyr10 and Tyr14) present in the N-terminal region of CCR5 (Fig.…”
Section: Resultsmentioning
confidence: 99%
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“…Despite their definition as variable loops, the V2 and V3 regions of gp120 contain highly conserved domains (33). Because several lines of evidence suggest that V3 establishes direct interaction with V2 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21), and the conserved base of V3 is the binding site for the N-terminal region of the CCR5 coreceptor (34), we looked for potential structural homology between V2 and CCR5. We recognized that the conserved central region of V2 contains two tyrosine residues (Tyr173 and Tyr177) with spacing identical to that of two tyrosines (Tyr10 and Tyr14) present in the N-terminal region of CCR5 (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Functional and antigenic interactions between V2 and V3 have long been recognized (21)(22)(23)(24)(25)(26)(27), and spatial proximity between these two loops has been documented by both cryo-EM studies (12)(13)(14)(15)(16)(17) and the recently solved crystal structure of a stabilized soluble SOSIP trimer at 4.7-Å resolution (18). Despite the lack of sulfated tyrosines (presumably because the soluble trimer was produced in HEK293 cells), the latter structure is consistent with our model because it shows the 173-177 segment of V2 directly juxtaposed to the CCR5-binding region at the base of V3, with the most conserved of the two sulfotyrosines, Tyr177, establishing van der Waals contacts with Ile420, Leu154, and Leu175, as well as an H-bond with Asn302, all residues that are proximal to the predicted binding pocket for the homologous sulfotyrosine (Tys14) of CCR5 (34).…”
Section: Discussionmentioning
confidence: 99%
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“…With the increasing understanding of the architecture of the viral spike (21,76,77), the possibility to generate stable soluble trimers that closely resemble the native spike (78,79), and the means to generate structurally arrested peptide mimetics of gp120 microdomains (31), a number of tools have become available which have promise to tailor future DARPin selections to specific domains of interest. As discussed above, based on our current data, this holds particular promise to improve envelope-specific DARPin identification and to harness the distinctive binding properties of DARPins for HIV inhibitor development.…”
Section: Discussionmentioning
confidence: 99%