V3 Loop

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Alexander M Andrianov - One of the best experts on this subject based on the ideXlab platform.

  • discovery of novel anti hiv 1 agents based on a broadly neutralizing antibody against the envelope gp120 V3 Loop a computational study
    Journal of Biomolecular Structure & Dynamics, 2014
    Co-Authors: Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
    Abstract:

    A computer-aided search for novel anti-HIV-1 agents able to mimic the pharmacophore properties of broadly neutralizing antibody (bNAb) 3074 was carried out based on the analysis of X-ray complexes of this antibody Fab with the MN, UR29, and VI191 peptides from the V3 Loop of the HIV envelope protein gp120. Using these empirical data, peptidomimetic candidates of bNAb 3074 were identified by a public, web-oriented virtual screening platform (pepMMsMIMIC) and models of these candidates bound to the above V3 peptides were generated by molecular docking. The docking calculations identified four molecules exhibiting a high affinity to all of the V3 peptides. These molecules were selected as the most probable peptidomimetics of bNAb 3074. Finally, the stability of the complexes of these molecules with the MN, UR29, and VI191 V3 peptides was estimated by molecular dynamics and free energy simulations. Specific binding to the V3 Loop was accomplished primarily by π–π interactions between the aromatic rings of the...

  • discovery of novel promising targets for anti aids drug developments by computer modeling application to the hiv 1 gp120 V3 Loop
    Journal of Chemical Information and Modeling, 2011
    Co-Authors: Alexander M Andrianov, Ivan Anishchenko, Alexander V Tuzikov
    Abstract:

    The V3 Loop on gp120 from HIV-1 is a focus of many research groups involved in anti-AIDS drug studies, because this region of the protein determines the preference of the virus for T-lymphocytes or...

  • human immunodeficiency virus 1 gp120 V3 Loop for anti acquired immune deficiency syndrome drug discovery computer aided approaches to the problem solving
    Expert Opinion on Drug Discovery, 2011
    Co-Authors: Alexander M Andrianov
    Abstract:

    Introduction: The V3 Loop on gp120 from HIV-1 is a focus of many research groups involved in anti-AIDS drug development because this region of the protein is the principal target for neutralizing antibodies and determines the preference of the virus for T-lymphocytes or primary macrophages. Areas covered: This review summarizes findings related to the 3D structure, conformational mobility, function, antigenicity and immunogenicity of the HIV-1 V3 Loop. Particular consideration is given to the V3 Loop core sequence Gly-Pro-Gly-Arg/Gln-Ala-Phe, which forms the HIV-1 gp120 immunogenic tip, the role of which has not been completely determined in the virus pathogenesis. New computer-aided approaches for designing potential HIV-1 entry inhibitors are illustrated by a series of examples in which promising basic structures for the V3-based anti-AIDS drug researches have been constructed. Special focus is given to recent studies aimed at defining the structurally conservative V3 sites that may present the HIV-1 we...

  • computational model of the hiv 1 subtype a V3 Loop study on the conformational mobility for structure based anti aids drug design
    Journal of Biomolecular Structure & Dynamics, 2009
    Co-Authors: Alexander M Andrianov, Ivan Anishchenko
    Abstract:

    Abstract The V3 Loop of the HIV-1gp120 glycoprotein presenting 35-residue-long, frequently glycosylated, highly variable, and disulfide bonded structure plays the central role in the virus biology and forms the principal target for neutralizing antibodies and the major viral determinant for co-receptor binding. Here we present the computer-aided studies on the 3D structure of the HIV-1 subtype A V3 Loop (SA-V3 Loop) in which its structurally inflexible regions and individual amino acids were identified and the structure-function analysis of V3 aimed at the informational support for anti-AIDS drug researches was put into practice. To this end, the following successive steps were carried out: (i) using the methods of comparative modeling and simulated annealing, the ensemble of the low-energy structures was generated for the consensus amino acid sequence of the SA-V3 Loop and its most probable conformation was defined basing on the general criteria widely adopted as a measure of the quality of protein struc...

  • immunophilins and hiv 1 V3 Loop for structure based anti aids drug design
    Journal of Biomolecular Structure & Dynamics, 2009
    Co-Authors: Alexander M Andrianov
    Abstract:

    Abstract The model of the structural complex of cyclophilin A (CycA) belonging to the immunophilins family with the HIV-MN gpl20 V3 Loop was generated, and the computer-aided design of the immunophilin-derived peptide able to mask the biologically crucial V3 segments was implemented. To this end, the following problems were solved: (i) the NMR-based conformational analysis of the HIV-MN V3 Loop was put into effect, and its low energy structure fitting the input experimental observations was determined; (ii) molecular docking of this V3 structure with the X-ray conformation of CycA was carried out, and the energy refining the simulated structural complex was performed; (iii) the matrix of inter-atomic distances for the amino acids of the molecules forming part of the built over-molecular ensemble was computed, the types of interactions responsible for its stabilization were analyzed, and the CycA stretch, which accounts for the binding to V3, was identified; (iv) the most probable 3D structure for this str...

Ian A Wilson - One of the best experts on this subject based on the ideXlab platform.

  • recurring conformation of the human immunodeficiency virus type 1 gp120 V3 Loop
    Virology, 2003
    Co-Authors: Robyn L Stanfield, Albert T Profy, J B Ghiara, Erica Ollmann Saphire, Ian A Wilson
    Abstract:

    The crystal structure of the human immunodeficiency virus type 1 (HIV-1) neutralizing, murine Fab 83.1 in complex with an HIV-1 gp120 V3 peptide has been determined to 2.57 A resolution. The conformation of the V3 Loop peptide in complex with Fab 83.1 is very similar to V3 conformations seen previously with two other neutralizing Fabs, 50.1 and 59.1. The repeated identification of this same V3 conformation in complex with three very different, neutralizing antibodies indicates that it is a highly preferred structure for V3 Loops on some strains of the HIV-1 virus.

  • dual conformations for the hiv 1 gp120 V3 Loop in complexes with different neutralizing fabs
    Structure, 1999
    Co-Authors: Robyn L Stanfield, Edelmira Cabezas, Arnold C Satterthwait, Enrico A Stura, Albert T Profy, Ian A Wilson
    Abstract:

    Abstract Background: The third hypervariable (V3) Loop of HIV-1 gp120 has been termed the principal neutralizing determinant (PND) of the virus and is involved in many aspects of virus infectivity. The V3 Loop is required for viral entry into the cell via membrane fusion and is believed to interact with cell surface chemokine receptors on T cells and macrophages. Sequence changes in V3 can affect chemokine receptor usage, and can, therefore, modulate which types of cells are infected. Antibodies raised against peptides with V3 sequences can neutralize laboratory-adapted strains of the virus and inhibit syncytia formation. Fab fragments of these neutralizing antibodies in complex with V3 Loop peptides have been studied by X-ray crystallography to determine the conformation of the V3 Loop. Results: We have determined three crystal structures of Fab 58.2, a broadly neutralizing antibody, in complex with one linear and two cyclic peptides the amino acid sequence of which comes from the MN isolate of the gp120 V3 Loop. Although the peptide conformations are very similar for the linear and cyclic forms, they differ from that seen for the identical peptide bound to a different broadly neutralizing antibody, Fab 59.1, and for a similar peptide bound to the MN-specific Fab 50.1. The conformational difference in the peptide is localized around residues Gly-Pro-Gly-Arg, which are highly conserved in different HIV-1 isolates and are predicted to adopt a type II β turn. Conclusions: The V3 Loop can adopt at least two different conformations for the highly conserved Gly-Pro-Gly-Arg sequence at the tip of the Loop. Thus, the HIV-1 V3 Loop has some inherent conformational flexibility that may relate to its biological function.

  • structure based design of a constrained peptide mimic of the hiv 1 V3 Loop neutralization site
    Journal of Molecular Biology, 1997
    Co-Authors: J B Ghiara, Arnold C Satterthwait, D C Ferguson, H J Dyson, Ian A Wilson
    Abstract:

    Abstract Antigenic variation among different HIV-1 isolates has been a major problem in the development of an effective vaccine against AIDS. Peptide vaccines incorporating structural elements common to groups of viral isolates, such as the clade subtypes of HIV-1, hold promise; however, the design of such immunogens has been hampered by the lack of specific structural information on the viral proteins to be targeted. As part of a structure-based approach to this problem, we report the design and characterization of a conformationally restricted peptide analog (Aib142) of a highly conserved HIV-1 clade-B sequence from the third variable Loop of the membrane glycoprotein gp120. The design strategy incorporates peptide conformational data derived from crystal structure analysis of an MN-isolate peptide (RP142) in complex with the Fab fragment (Fab59.1) of a broadly neutralizing antibody. The synthetic peptide (Aib142) replaces an alanine residue within the V3 Loop epitope sequence GPGRAF by the conformationally restricted helicogenic α-aminoisobutyryl residue. As expected, the crystal structure of the Fab 59.1-Aib142 complex at 2.8 A resolution shows that the peptide interacts very similarly with the neutralizing antibody. Proton nuclear magnetic resonance (NMR) studies indicate that the free Aib142 peptide is indeed more ordered in solution with a conformational preference that corresponds to the X-ray structure of its Fab-bound form. Aib142 thus represents the first step in the design of conformationally constrained peptide analogs built to mimic biologically relevant structural forms of HIV-1 neutralization sites.

  • crystal structure of a human immunodeficiency virus type 1 neutralizing antibody 50 1 in complex with its V3 Loop peptide antigen
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: James M Rini, Robyn L Stanfield, Enrico A Stura, Albert T Profy, Paul Salinas, Ian A Wilson
    Abstract:

    The crystal structure of the Fab fragment of a human immunodeficiency virus type 1 (HIV-1) neutralizing monoclonal antibody Fab has been determined at 2.8 A resolution in complex with a linear 16-residue peptide from the third hypervariable region (V3) of gp120. The first 9 residues of the peptide are ordered in the electron density maps, and their conformation is in partial agreement with the beta-strand-type II beta-turn structure predicted for this portion of the V3 Loop. Notably, several of the peptide residues that are well conserved among different HIV-1 isolates contact a nonpolar 25-A-long groove in the antibody-combining site. The largely extended structure of the peptide differs from the beta-turns seen as the primary determinants in other published anti-peptide Fab structures. Analysis of the specific Fab-peptide interactions only partially explains the MN isolate specificity shown by this antibody.

Xiaowei Jiang - One of the best experts on this subject based on the ideXlab platform.

  • protein structural disorder of the envelope V3 Loop contributes to the switch in human immunodeficiency virus type 1 cell tropism
    PLOS ONE, 2017
    Co-Authors: Felix Feyertag, Xiaowei Jiang, David L Robertson
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV’s life cycle, particularly, V3 Loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this ‘rewiring’ event occur in HIV-1 infected patients? As changes in the charge of the V3 Loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 Loop is permissive to sequence variation thus contributing to the switch in cell tropism. To test this we use three independent data sets of gp120 to analyse V3 Loop disorder. We find that the V3 Loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in HIV-1 cell tropism and CXCR4 binding. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation.

  • protein structural disorder of the envelope V3 Loop contributes to the switch in human immunodeficiency virus type 1 cell tropism
    bioRxiv, 2017
    Co-Authors: Xiaowei Jiang, Felix Feyertag, David L Robertson
    Abstract:

    Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV9s life cycle, particularly, V3 Loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections. Why does this ‘rewiring’ event occur in HIV-1 infected patients? As changes in the charge of the V3 Loop are associated with this receptor switch and it has been suggested that charged residues promote structure disorder, we hypothesise that the intrinsic disorder of the V3 Loop plays a role in determining cell tropism. To test this we use three independent data sets of gp120 to analyse V3 Loop disorder. We find that the V3 Loop of X4 virus has significantly higher intrinsic disorder tendency than R5 and R5X4 virus, while R5X4 virus has the lowest. These results indicate that structural disorder plays an important role in determining HIV-1 cell tropism and CXCR4 binding. We speculate that changes in N-linked glycosylation associated with tropism change (from R5 to X4) are required to stabilise the V3 Loop with increased disorder tendency during HIV-1 evolution. We discuss the potential evolutionary mechanisms leading to the fixation of disorder promoting mutations and the adaptive potential of protein structural disorder in viral host adaptation.

Cecilia Chengmayer - One of the best experts on this subject based on the ideXlab platform.

  • the n terminal V3 Loop glycan modulates the interaction of clade a and b human immunodeficiency virus type 1 envelopes with cd4 and chemokine receptors
    Journal of Virology, 2000
    Co-Authors: Susan E Malenbaum, James E Robinson, Lisa A Cavacini, Marshall R Posner, David Yang, Cecilia Chengmayer
    Abstract:

    We investigated the underlying mechanism by which the highly conserved N-terminal V3 Loop glycan of gp120 conferred resistance to neutralization of human immunodeficiency virus type 1 (HIV-1). We find that the presence or absence of this V3 glycan on clade A and B viruses accorded various degrees of susceptibility to neutralization by antibodies to the CD4 binding site, CD4-induced epitopes, and chemokine receptors. Our data suggest that this carbohydrate moiety on gp120 blocks access to the binding site for CD4 and modulates the chemokine receptor binding site of phenotypically diverse clade A and clade B isolates. Its presence also contributes to the masking of CD4-induced epitopes on clade B envelopes. These findings reveal a common mechanism by which diverse HIV-1 isolates escape immune recognition. Furthermore, the observation that conserved functional epitopes of HIV-1 are more exposed on V3 glycan-deficient envelope glycoproteins provides a basis for exploring the use of these envelopes as vaccine components.

  • structural modulations of the envelope gp120 glycoprotein of human immunodeficiency virus type 1 upon oligomerization and differential V3 Loop epitope exposure of isolates displaying distinct tropism upon virion soluble receptor binding
    Journal of Virology, 1995
    Co-Authors: L Stamatatos, Cecilia Chengmayer
    Abstract:

    We investigated the binding of conformation-dependent anti-V2, anti-V3, and anti-CD4-binding site monoclonal antibodies to monomeric and virion-associated gp120 from human immunodeficiency virus type 1 isolates displaying marked differences in cell tropism. For all viruses examined, we found that the half-maximal binding values of the anti-V2 and anti-CD4-binding site antibodies with virion-associated gp120 were higher than those with monomeric gp120, but the maximum amount of antibodies bound was diminished only for one of the anti-V2 antibodies tested. These observations suggest that upon gp120 oligomerization, the V2 Loop and CD4-binding site undergo conformational changes and that particular epitopes within these domains are occluded in the oligomeric gp120. In contrast, although the overall binding patterns and half-maximal binding values of the anti-V3 Loop antibodies tested were similar with monomeric and oligomeric gp120, all the V3 Loop epitopes examined were less accessible to antibody binding on the virion surface. This masking of the V3 Loop is more pronounced for the primary-like macrophage-tropic isolates examined. Lastly, we observe that upon soluble receptor-virion binding, specific V3 Loop epitopes that differ for viruses displaying different tropisms are exposed.

  • amino acid substitutions in the V3 Loop are responsible for adaptation to growth in transformed t cell lines of a primary human immunodeficiency virus type 1
    Virology, 1995
    Co-Authors: Gregory Harrowe, Cecilia Chengmayer
    Abstract:

    A T-cell-line-tropic, syncytium-inducing, sCD4- and serum neutralization-sensitive variant (R3H) of the macrophage-tropic, non-syncytium-inducing, sCD4- and serum neutralization-resistant molecular clone HIV-1SF162 was obtained by passage through the T-cell line HUT 78. Sequence analyses of the V1-V5 regions of envelope gp120 of the variant R3H revealed amino acid substitutions in the V3 (amino acids 307, 312) and V4 (amino acid 390) domains. Site-directed mutagenesis of the HIV-1SF162 genome showed that specific mutations in the V3 Loop of this isolate can alter tropism and cytopathicity of the virus, but only moderately affect its sensitivity to sCD4 and serum neutralization. These results show that adaptation to growth in T-cell lines can render a primary-like virus sensitive to sCD4 and serum neutralization. However, the extent of T-cell line tropism does not correlate with the degree of susceptibility to sCD4 and serum neutralization. The latter appears to be dependent on the amino acid compositions of the V3 Loop and other regions of envelope gp120, whereas the former is primarily determined by the V3 Loop. Our findings further illustrate the importance of the V3 Loop in influencing HIV-1 cell tropism and syncytium formation, and the interplay among V3 Loop residues in maintaining a structure of the Loop that influences biological phenotype of the virus.

Alexander V Tuzikov - One of the best experts on this subject based on the ideXlab platform.