NMR structure of an anti-gp120 antibody complex with a V3 peptide reveals a surface important for co-receptor binding

Tugarinov, Vitali; Zvi, Anat; Levy, Rina; Hayek, Joussef; Matsushita, Shuzo; Anglister, Jacob

doi:10.1016/s0969-2126(00)00119-2

Cited by 62 publications

(62 citation statements)

References 71 publications

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“…Sharon et al (17) report that the N-terminal strand and four residues from the C-terminal strand contribute to almost all the interactions between the V3 loop and the 447 Fv antibody, whereas in Stanfield et al (12), sequence specificity is conferred through interaction of the type-II turn at the apex of the V3 hairpin. Another study using an 18-residue HIV-1 V3 peptide in complex with a fragment of an anti-gp120 antibody revealed a ␤-turn comprising residues RGPG at the center of the ␤-hairpin (18). The central glycine and proline residues of this turn were found to be linked by a cis-peptide bond; however, we found no evidence for a cis-peptide bond in the present study.…”

Section: Discussioncontrasting

confidence: 83%

Interaction of the HIV-1 gp120 Viral Protein V3 Loop with Bacterial Lipopolysaccharide

Majerle¹,

Pristovšek

Manček-Keber³

et al. 2011

Journal of Biological Chemistry

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Section: Discussioncontrasting

confidence: 83%

Interaction of the HIV-1 gp120 Viral Protein V3 Loop with Bacterial Lipopolysaccharide

Majerle¹,

Pristovšek

Manček-Keber³

et al. 2011

Journal of Biological Chemistry

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“…The region of the Fv-bound V3 JR-FL for which we obtained a well defined structure includes residues R304 and E322, the latter of which is known to be critical for phenotype conversion. These residues were not ordered in any of the three structures of antibody-bound V3 peptides that we previously reported (6,10,11). The short distance, 4.6 Å, between the positively charged guanidinium proton of R304 and the negatively charged oxygen of the E322 carboxyl suggests the existence of an electrostatic interaction between these two residues.…”

Section: Resultsmentioning

confidence: 73%

Molecular switch for alternative conformations of the HIV-1 V3 region: Implications for phenotype conversion

Rosen

Sharon

Quadt-Akabayov

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 coreceptor usage plays a critical role in virus tropism and pathogenesis. A switch from CCR5-to CXCR4-using viruses occurs during the course of HIV-1 infection and correlates with subsequent disease progression. A single mutation at position 322 within the V3 loop of the HIV-1 envelope glycoprotein gp120, from a negatively to a positively charged residue, was found to be sufficient to switch an R5 virus to an X4 virus. In this study, the NMR structure of the V3 region of an R5 strain, HIV-1JR-FL, in complex with an HIV-1-neutralizing antibody was determined. Positively charged and negatively charged residues at positions 304 and 322, respectively, oppose each other in the ␤-hairpin structure, enabling a favorable electrostatic interaction that stabilizes the postulated R5 conformation. Comparison of the R5 conformation with the postulated X4 conformation of the V3 region (positively charged residue at position 322) reveals that electrostatic repulsion between residues 304 and 322 in X4 strains triggers the observed one register shift in the N-terminal strand of the V3 region. We posit that electrostatic interactions at the base of the V3 ␤-hairpin can modulate the conformation and thereby influence the phenotype switch. In addition, we suggest that interstrand cation-interactions between positively charged and aromatic residues induce the switch to the X4 conformation as a result of the S306R mutation. The existence of three pairs of identical (or very similar) amino acids in the V3 C-terminal strand facilitates the switch between the R5 and X4 conformations.447-52D ͉ gp120 ͉ NMR T he third variable (V3) region of the HIV type 1 (HIV-1) envelope glycoprotein gp120 binds to chemokine receptors CCR5 and CXCR4, which are involved in HIV-1 infection. The amino acid sequence of V3 determines whether the virus binds to CCR5 (''R5 viruses'') and infects predominantly macrophages or to CXCR4 (''X4 viruses'') and infects mostly T cells (1). The presence of a basic residue at V3 positions 306 or 322 is associated with X4 and dual-tropic, X4R5 viruses, whereas the presence of a negatively charged residue and a neutral residue at positions 322 and 306, respectively, is correlated with R5 viruses (the ''11͞25 rule'') (2). Numerous investigations have confirmed that mutation of a negatively charged residue at position 322 to a positively charged one converts an R5 strain into an X4 strain (2-4).To gain insight into the structure of the V3 region and the mechanism for phenotype conversion, we used solution NMR spectroscopy to study the conformation of synthetic V3 peptides in complex with V3-specific anti-gp120 antibodies. An assumption underlying this approach is that the native conformation of V3 is induced in linear V3 peptides upon binding to V3-directed antibodies that were elicited against the entire gp120 protein. We studied two V3-specific antibodies. The first, murine mAb 0.5␤, is a potent strain-specific HIV-1-neutralizing antibody that was raised against a full-length gp120 protein of the X4 virus HIV-1 IIIB (...

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“…The tip of the V3 loop is thought to contain a ␤-turn, based upon the presence of a highly conserved glycine-proline-glycine motif and upon X-ray crystal and nuclear magnetic resonance structures of V3 peptides complexed with Abs (26,61,67). Residue 315, which immediately follows this ␤-turn, is either an arginine or glutamine in both X4 and R5 HIV-1 isolates (39).…”

Section: Discussionmentioning

confidence: 99%

Identification of Conserved and Variable Structures in the Human Immunodeficiency Virus gp120 Glycoprotein of Importance for CXCR4 Binding

Basmaciogullari

Babcock

Ryk

et al. 2002

J Virol

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CD4 and the chemokine receptors, CXCR4 and CCR5, serve as receptors for human immunodeficiency virus type 1 (HIV-1). Binding of the HIV-1 gp120 envelope glycoprotein to the chemokine receptors normally requires prior interaction with CD4. Mapping the determinants on gp120 for the low-affinity interaction with CXCR4 has been difficult due to the nonspecific binding of this viral glycoprotein to cell surfaces. Here we examine the binding of a panel of gp120 mutants to paramagnetic proteoliposomes displaying CXCR4 on their surfaces. We show that the gp120 ␤19 strand and third variable (V3) loop contain residues important for CXCR4 interaction. Basic residues from both elements, as well as a conserved hydrophobic residue at the V3 tip, contribute to CXCR4 binding. Removal of the gp120 V1/V2 variable loops allows the envelope glycoprotein to bind CXCR4 in a CD4-independent manner. These results indicate that although some variable gp120 residues contribute to the specific binding to CCR5 or CXCR4, gp120 elements common to CXCR4-or CCR5-using strains are involved in the interaction with both coreceptors.

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NMR structure of an anti-gp120 antibody complex with a V3 peptide reveals a surface important for co-receptor binding

Cited by 62 publications

References 71 publications

Interaction of the HIV-1 gp120 Viral Protein V3 Loop with Bacterial Lipopolysaccharide

Interaction of the HIV-1 gp120 Viral Protein V3 Loop with Bacterial Lipopolysaccharide

Molecular switch for alternative conformations of the HIV-1 V3 region: Implications for phenotype conversion

Identification of Conserved and Variable Structures in the Human Immunodeficiency Virus gp120 Glycoprotein of Importance for CXCR4 Binding

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