PMID:15657041

Citation	Hamburger, AE, Kim, S, Welch, BD and Kay, MS (2005) Steric accessibility of the HIV-1 gp41 N-trimer region. J. Biol. Chem. 280:12567-72
Abstract	During human immunodeficiency virus entry, gp41 undergoes a series of conformational changes that induce membrane fusion. Immediately prior to fusion, gp41 exists in a prehairpin intermediate in which the N- and C-peptide regions of gp41 are exposed. Rearrangement of this intermediate into a six-helix bundle composed of a trimeric coiled coil from the N-peptide region (N-trimer) surrounded by three peptides from the C-peptide region provides the driving force for membrane fusion, whereas prevention of six-helix bundle formation inhibits viral entry. Because of its central role in mediating viral entry, the N-trimer region of gp41 is a key vaccine target. Extensive efforts to discover potent and broadly neutralizing antibodies (Abs) against the N-trimer region have, thus far, been unsuccessful. In this study, we attached a potent C-peptide inhibitor that binds to the N-trimer region to cargo proteins of various sizes to examine the steric accessibility of the N-trimer during fusion. These inhibitors show a progressive loss of potency with increasing cargo size. Extension of the cargo/C-peptide linker partially restores inhibitory potency. These results demonstrate that the human immunodeficiency virus defends its critical hairpin-forming machinery by steric exclusion of large proteins and may explain the current dearth of neutralizing Abs against the N-trimer. In contrast, previous results suggest the C-peptide region is freely accessible during fusion, demonstrating that the N- and C-peptide regions are in structurally distinct environments. Based on these results, we also propose new strategies for the generation of neutralizing Abs that overcome this steric block.
Links	PubMed Online version:10.1074/jbc.M412770200
Keywords	Antibodies, Monoclonal/chemistry; Cell Fusion; Dimerization; Dose-Response Relationship, Drug; Enzyme Inhibitors/pharmacology; HIV Envelope Protein gp41/chemistry; HIV Envelope Protein gp41/physiology; Humans; Inhibitory Concentration 50; Models, Biological; Peptides/chemistry; Plasmids/metabolism; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Proteins/chemistry; Stereoisomerism; Surface Plasmon Resonance; Time Factors; Ultraviolet Rays
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