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Updated: Aug 1, 2026
Determination of Molecular Structures of HIV Envelope Glycoproteins using Cryo-Electron Tomography and Automated Sub-tomogram Averaging
Published on: December 1, 2011
Biophysical studies of HIV-1 glycoprotein-41 interactions with peptides and small molecules - Effect of lipids and
Guangyan Zhou1, Shidong Chu1, Aditya Kohli2
1Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, United States of America.
Background:
The hydrophobic pocket (HP) of HIV-1 glycoprotein-41 ectodomain is defined by two chains of the N-heptad repeat trimer, within the protein-protein interface that mediates 6HB formation. It is a potential target for inhibitors of viral fusion, but its hydrophobic nature and proximity to membrane in situ has precluded ready analysis of inhibitor interactions.
Methods:
We evaluated the sensitivity of 19F NMR and fluorescence for detecting peptide and small molecule binding to the HP and explored the effect of non-denaturing detergent or phospholipid as cosolvents and potential mimics of the membrane environment surrounding gp41.
Results:
Chemical shifts of aromatic fluorines were found to be sensitive to changes in the hydrogen bonding network that occurred when inhibitors transitioned from solvent into the HP or into ordered detergent micelles. Fluorescence intensities and emission maxima of autofluorescent compounds responded to changes in the local environment.
Conclusions:
Gp41 - ligand binding occurred under all conditions, but was diminished in the presence of detergents. NMR and fluorescence studies revealed that dodecylphosphocholine (DPC) was a poor substitute for membrane in this system, while liposomes could mimic the membrane surroundings.
General Significance:
Our findings suggest that development of high potency small molecule binders to the HP may be frustrated by competition between binding to the HP and binding to the bilayer membrane.
