Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, JFB 824, Boston, MA 02115, USA.
Structure (Impact Factor: 6.79). 12/2008; 16(11):1689-701. DOI: 10.1016/j.str.2008.09.005
Source: PubMed

ABSTRACT Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.

Download full-text


Available from: Arne Schon, Apr 25, 2014
  • Source
    • "Binding CD4 creates the " Phe 43 cavity " , an interfacial cavity bounded by all three gp120 domains and by phenylalanine 43 of CD4. The walls of the Phe 43 cavity are lined by well-conserved gp120 residues, rendering it suitable as a target for small-molecule inhibitors (Madani et al., 2008). Interventional approaches targeting the CD4-binding site, using either antibodies or small molecules, would benefit from a better understanding of the conformational transitions involved in receptor binding. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The entry of human immunodeficiency virus (HIV-1) into cells is initiated by binding of the gp120 exterior envelope glycoprotein to the receptor, CD4. How does CD4 binding trigger conformational changes in gp120 that allow the gp41 transmembrane envelope glycoprotein to mediate viral-cell membrane fusion? The transition from the unliganded to the CD4-bound state is regulated by two potentially flexible topological layers (layers 1 and 2) in the gp120 inner domain. Both layers apparently contribute to the noncovalent association of unliganded gp120 with gp41. After CD4 makes initial contact with the gp120 outer domain, layer 1-layer 2 interactions strengthen gp120-CD4 binding by reducing the off rate. Layer 1-layer 2 interactions also destabilize the activated state induced on HIV-1 by treatment with soluble CD4. Thus, despite lack of contact with CD4, the gp120 inner-domain layers govern CD4 triggering by participating in conformational transitions within gp120 and regulating the interaction with gp41.
    Molecular cell 03/2010; 37(5):656-67. DOI:10.1016/j.molcel.2010.02.012 · 14.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The 24h molecular clock that ticks in organisms from bacteria to humans is useless without an output signal. The 18 amino acid neuropeptide, the pigment dispersing factor (PDF) encoded by the pdf gene, is the key outgoing signal in behavioral circadian rhythms in Drosophila melanogaster. PDF is likely to act on clock neurons in an autocrine or paracrine fashion. In this study, we identify the PDF receptor, which belongs to the G-protein coupled receptor family. We cloned the ORF of gene CG13758 and this resulted in a gene product of 669 amino acids, which did not correspond to the predicted protein length in the Drosophila database. Functional expression of this orphan receptor in HEK-293 cells and screening with a synthetic peptide library revealed that Drm-PDF specifically activates the receptor in a dose-dependent way. No other peptides were able to elicit a calcium response. These results indicate that we have cloned and identified the Drosophila PDF receptor.
Show more