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