Conformational rearrangements required of the V<sub>3</sub> loop of HIV‐1 gp120 for proteolytic cleavage and infection

Johnson, Michael E.; Lin, Zhaolan; Padmanabhan, K.; Tulinsky, A.; Kahn, Michaël

doi:10.1016/0014-5793(94)80618-7

Cited by 33 publications

(27 citation statements)

References 38 publications

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“…5023A/5025A binding to this region may prohibit important co-receptor interactions involving these conserved gp120 residues. Another potential function of this conserved residue sequence may be that it serves as a recognition site for proteolysis of the V3 loop; specific cleavage of the V3 loop has been postulated to precede the cell membrane fusion events required for virus infection (61,(65)(66)(67). Flexibility of the V3 loop, especially involving the GPGR residues, would also be beneficial in this situation (66).…”

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

“…Another potential function of this conserved residue sequence may be that it serves as a recognition site for proteolysis of the V3 loop; specific cleavage of the V3 loop has been postulated to precede the cell membrane fusion events required for virus infection (61,(65)(66)(67). Flexibility of the V3 loop, especially involving the GPGR residues, would also be beneficial in this situation (66). For this latter possibility, 5023A/5025A binding to a particular region of the V3 loop could serve to prohibit access to this critical cleavage site (68).…”

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

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The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Wu¹,

MacKenzie²,

Durda³

et al. 2000

Journal of Biological Chemistry

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The structural and antigenic properties of a peptide ("CRK") derived from the V3 loop of HIV-1 gp120 protein were studied using NMR and SPR techniques. The sequence of CRK corresponds to the central portion of the V3 loop containing the highly conserved "GPGR" residue sequence. Although the biological significance of this conserved sequence is unknown, the adoption of conserved secondary structure (type II ␤-turn) in this region has been proposed. The tendency of CRK (while free or conjugated to protein), to adopt such structure and the influence of such structure upon CRK antigenicity were investigated by NMR and SPR, respectively. Regardless of conjugation, CRK is conformationally averaged in solution but a weak tendency of the CRK "GPGR" residues to adopt a ␤-turn conformation was observed after conjugation. The influence of GPGR structure upon CRK antigenicity was investigated by measuring the affinities of two cognate antibodies: "5023A" and "5025A," for CRK, protein-conjugated CRK and gp120 protein. Each antibody bound to all the antigens with nearly the same affinity. From these data, it appears that: (a) antibody binding most likely involves an induced fit of the peptide and (b) the gp120 V3 loop is probably conformationally heterogeneous. Since 5023A and 5025A are HIV-1 neutralizing antibodies, neutralization in these cases appears to be independent of adopted GPGR ␤-turn structure. The principal neutralizing determinant (PND)1 of HIV-1 has been mapped to the third hypervariable (V3) loop of the HIV-1 envelope protein, gp120 (1). PND-derived peptides are used as immunogens to elicit antibodies that possess HIV-1 virus neutralization capabilities (2, 3). The binding of neutralizing antibodies blocks virus entry into the host cell but does not prevent binding of HIV-1 to its primary cell receptor protein, CD4 (4, 5). Although the V3 loop represents an important target for the development of vaccines against AIDS, its high sequence variability also makes it a very problematic one (6). Nonetheless, the occurrence of the highly conserved residue sequence, "GPGR," at the tip of the V3 loop has raised the possibility that these residues make up a conserved secondary structural element in gp120. The function of such a structural element, if one exists, is presently unknown, however. The precise predicted secondary structure adopted by the GPGR residues is a type II ␤-turn (6, 7).In order to determine whether the conserved GPGR sequence confers certain secondary structural tendencies upon this region of the V3 loop, numerous NMR studies were conducted upon a variety of V3 loop-derived peptides (8 -21). These peptides were shown to have only low density populations of folded structure and to be conformationally averaged in solution. Despite the report of a "core" gp120 protein complex crystal structure, this complex was prepared using a form of gp120 which lacked most of the hypervariable loops including V3 (22). Information regarding the actual three-dimensional structure of the V3 loop in native gp120 is theref...

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Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Wu¹,

MacKenzie²,

Durda³

et al. 2000

Journal of Biological Chemistry

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“…[11] Johnson et al proposed that a trans/cis isomerization towards a type VI b-turn with a cis-proline peptide bond is a necessary conformational change for cleavage and subsequent fusion. [12] Other indications of the importance of conformational changes in gp120 preceding infection have recently appeared, [13,14] and a type VI b-turn conformation has been observed in a peptide derived from the HIV-1 IIIB V3 loop when bound to an anti-gp120 antibody. [15] Here, we have targeted the proposed infection-active cis conformation by preparing pseudoproline-containing, cis-constrained V3 loop analogues as immunogens.…”

mentioning

confidence: 99%

Pseudoprolines: Targeting acis Conformation in a Mimetic of the gp120 V3 Loop of HIV-1

Wittelsberger

Keller

Scarpellino

et al. 2000

Angew. Chem. Int. Ed.

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The specific recognition of cis peptide bonds is possible with antibodies that are directed against cyclic and linear peptide antigens derived from the V3 loop of the HIV‐1 protein gp120, into which a thiazolidine derivative (pseudoproline) has been introduced (see schematic representation). This extension of the pseudoproline concept may help to decipher the unique role of proline residues in biologically relevant systems.

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“…The NMR studies were carried out on a Bruker AM400 spectrometer in either CDC13 or CD3OD at 25 °C. Minimum energy conformers of the mimetic were found by a Monte Carlo search with the MacroModel program BATCHMIN [6]. A modified MacroModel MM2 force field, in which the N(sp2)-N(sp 2) force constant was adapted from the AMBER force field, was used for the calculations.…”

Section: Methodsmentioning

confidence: 99%

“…Based upon our previous analysis [6], we have designed and synthesized a constrained B-cell epitope library incorporating both the B (before binding) and A (after binding) type constructions (Fig. 2).…”

Section: Vaccinesmentioning

confidence: 99%

Pharmaceutical applications of peptidomimetics

et al. 1996

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Nature has used a 'library approach' to constructing ligands for specific receptors and enzymes by combining a limited functional diversity of 20 amino acid side chains with a small array of secondary structure motifs -reverse turns, co-helices and [3-strands. The dissection of multidomain proteins into small synthetic conformationally restricted components is an important step in the design of low-molecular-weight nonpeptides that mimic the activity of the native protein. Mimetics of critical functional domains might possess beneficial properties with regard to specificity and therapeutic potential compared to the intact proteinaceous species. Combinatorial secondarystructure-templated libraries provide a powerful engine for the development of novel vaccines and pharmaceuticals.

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Conformational rearrangements required of the V₃ loop of HIV‐1 gp120 for proteolytic cleavage and infection

Cited by 33 publications

References 38 publications

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Pseudoprolines: Targeting acis Conformation in a Mimetic of the gp120 V3 Loop of HIV-1

Pharmaceutical applications of peptidomimetics

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Conformational rearrangements required of the V3 loop of HIV‐1 gp120 for proteolytic cleavage and infection

Cited by 33 publications

References 38 publications

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Pseudoprolines: Targeting acis Conformation in a Mimetic of the gp120 V3 Loop of HIV-1

Pharmaceutical applications of peptidomimetics

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Conformational rearrangements required of the V₃ loop of HIV‐1 gp120 for proteolytic cleavage and infection