The C34 Peptide Fusion Inhibitor Binds to the Six-Helix Bundle Core Domain of HIV-1 gp41 by Displacement of the C-Terminal Helical Repeat Region

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• 作者：John M. Louis ; James L. Baber ; G. Marius Clore
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：November 17, 2015
• 年：2015
• 卷：54
• 期：45
• 页码：6796-6805
• 全文大小：509K
• ISSN：1520-4995

文摘

The conformational transition of the core domain of HIV-1 gp41 from a prehairpin intermediate to a six-helix bundle is responsible for virus鈥揷ell fusion. Several inhibitors which target the N-heptad repeat helical coiled-coil trimer that is fully accessible in the prehairpin intermediate have been designed. One such inhibitor is the peptide C34 derived from the C-heptad repeat of gp41 that forms the exterior of the six-helix bundle. Here, using a variety of biophysical techniques, including dye tagging, size-exclusion chromatography combined with multiangle light scattering, double electron鈥揺lectron resonance EPR spectroscopy, and circular dichroism, we investigate the binding of C34 to two six-helix bundle mimetics comprising N- and C-heptad repeats either without (core^SP) or with (core^S) a short spacer connecting the two. In the case of core^SP, C34 directly exchanges with the C-heptad repeat. For core^S, up to two molecules of C34 bind the six-helix bundle via displacement of the C-heptad repeat. These results suggest that fusion inhibitors such as C34 can target a continuum of transitioning conformational states from the prehairpin intermediate to the six-helix bundle prior to the occurrence of irreversible fusion of viral and target cell membranes.