Download MendeleyCharacterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino terminal heptad repeat.
Izumi, K., Nakamura, S., Nakano, H., Shimura, K., Sakagami, Y., Oishi, S., Uchiyama, S., Ohkubo, T., Kobayashi, Y., Fujii, N., Matsuoka, M., Kodama, E.N.(2010) Antiviral Res
- PubMed: 20438763
- DOI: https://doi.org/10.1016/j.antiviral.2010.04.011
- Primary Citation of Related Structures:
3AHA - PubMed Abstract:
A transmembrane glycoprotein of HIV-1, gp41, plays a central role in membrane fusion of HIV-1 and host cells. Peptides derived from the amino- and carboxyl-terminal heptad repeat (N-HR and C-HR, respectively) of gp41 inhibit this fusion. The mechanism of resistance to enfuvirtide, a C-HR-derived peptide, is well defined; however the mechanism of resistance to N-HR-derived peptides remains unclear. We characterized an HIV-1 isolate resistant to the N-HR-derived peptide, N36. This HIV-1 acquired a total of four amino acid substitutions, D36G, N126K and E137Q in gp41, and P183Q in gp120. Among these substitutions, N126K and/or E137Q conferred resistance to not only N36, but also C34, which is the corresponding C-HR-derived peptide fusion inhibitor. We performed crystallographic and biochemical analysis of the 6-helix bundle formed by synthetic gp41-derived peptides containing the N126K/E137Q substitutions. The structure of the 6-helix bundle with N126K/E137Q was identical to that in wild-type HIV-1 except for the presence of a new hydrogen bond. Denaturing experiments revealed that the stability of the 6-helix bundle of N126K/E137Q is greater than in the wild-type. These results suggest that the stabilizing effect of N126K/E137Q provides resistance to N36 and C34.
Organizational Affiliation:
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
