scholarly journals Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

2012 ◽  
Vol 8 ◽  
pp. 1858-1866 ◽  
Author(s):  
Julia Meier ◽  
Kristin Kassler ◽  
Heinrich Sticht ◽  
Jutta Eichler
Keyword(s):  
Amino Acids ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Conformational Stability ◽  
Cellular Receptor ◽  
Binding Assays ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Hiv 1

Based on the structure of the HIV-1 glycoprotein gp120 in complex with its cellular receptor CD4, we have designed and synthesized peptides that mimic the binding site of CD4 for gp120. The ability of these peptides to bind to gp120 can be strongly enhanced by increasing their conformational stability through cyclization, as evidenced by binding assays, as well as through molecular-dynamics simulations of peptide–gp120 complexes. The specificity of the peptide–gp120 interaction was demonstrated by using peptide variants, in which key residues for the interaction with gp120 were replaced by alanine or D-amino acids.

scholarly journals Heparan Sulfate Targets the HIV-1 Envelope Glycoprotein gp120 Coreceptor Binding Site

2005 ◽  
Vol 280 (22) ◽  
pp. 21353-21357 ◽  
Author(s):  
Romain R. Vivès ◽  
Anne Imberty ◽  
Quentin J. Sattentau ◽  
Hugues Lortat-Jacob
Keyword(s):  
Heparan Sulfate ◽  
Binding Site ◽  
Envelope Glycoprotein ◽  
Envelope Glycoprotein Gp120 ◽  
Coreceptor Binding ◽  
Glycoprotein Gp120 ◽  
Hiv 1 ◽  
Coreceptor Binding Site

scholarly journals Structural Basis for Species Selectivity in the HIV-1 gp120-CD4 Interaction: Restoring Affinity to gp120 in Murine CD4 Mimetic Peptides

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Kristin Kassler ◽  
Julia Meier ◽  
Jutta Eichler ◽  
Heinrich Sticht
Keyword(s):  
Salt Bridge ◽  
Disulfide Bridge ◽  
Structural Basis ◽  
Binding Assays ◽  
Viral Glycoprotein ◽  
Gp120 Binding ◽  
C Terminus ◽  
Glycoprotein Gp120 ◽  
Dynamics Simulations ◽  
Hiv 1

The first step of HIV-1 infection involves interaction between the viral glycoprotein gp120 and the human cellular receptor CD4. Inhibition of the gp120-CD4 interaction represents an attractive strategy to block HIV-1 infection. In an attempt to explore the known lack of affinity of murine CD4 to gp120, we have investigated peptides presenting the putative gp120-binding site of murine CD4 (mCD4). Molecular modeling indicates that mCD4 protein cannot bind gp120 due to steric clashes, while the larger conformational flexibility of mCD4 peptides allows an interaction. This finding is confirmed by experimental binding assays, which also evidenced specificity of the peptide-gp120 interaction. Molecular dynamics simulations indicate that the mCD4-peptide stably interacts with gp120 via an intermolecular β-sheet, while an important salt-bridge formed by a C-terminal lysine is lost. Fixation of the C-terminus by introducing a disulfide bridge between the N- and C-termini of the peptide significantly enhanced the affinity to gp120.

scholarly journals In vivo alteration of humoral responses to HIV-1 envelope glycoprotein gp120 by antibodies to the CD4-binding site of gp120

Virology ◽  
2008 ◽  
Vol 372 (2) ◽  
pp. 409-420 ◽  
Author(s):  
Maria Luisa Visciano ◽  
Michael Tuen ◽  
Miroslaw K. Gorny ◽  
Catarina E. Hioe
Keyword(s):  
Binding Site ◽  
Envelope Glycoprotein ◽  
Envelope Glycoprotein Gp120 ◽  
Cd4 Binding Site ◽  
Glycoprotein Gp120 ◽  
Humoral Responses ◽  
Hiv 1

scholarly journals Ion-water coupling controls class A GPCR signal transduction pathways

2020 ◽  
Author(s):  
Neil J. Thomson ◽  
Owen N. Vickery ◽  
Callum M. Ives ◽  
Ulrich Zachariae
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Signal Transmission ◽  
Water Molecules ◽  
Long Distance ◽  
Protein Binding Region ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Extracellular Sodium ◽  
Communication Pathway

G-protein-coupled receptors (GPCRs) transmit signals across the cell membrane, forming the largest family of membrane proteins in humans. Most GPCRs activate through an evolutionarily conserved mechanism, which involves reorientation of helices and key residues, rearrangement of a hydrogen bonding network mediated by water molecules, and the expulsion of a sodium ion from a protonatable binding site. However, how these components interplay to engage the signal effector binding site remains elusive. Here, we applied information theory to molecular dynamics simulations of pharmaceutically important GPCRs to trace concerted conformational variations across the receptors. We discovered a conserved communication pathway that includes protein residues and cofactors and enables the exchange of information between the extracellular sodium binding site and the intracellular G-protein binding region, coupling the most highly conserved protonatable residues at long distance. Reorientation of internal water molecules was found to be essential for signal transmission along this pathway. By inhibiting protonation, sodium decoupled this connectivity, identifying the ion as a master switch that determines the receptors’ ability to move towards active conformations.

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