3AHA

Crystal structure of the complex between gp41 fragments N36 and C34 mutant N126K/E137Q

Summary for 3AHA

• Entry DOI: 10.2210/pdb3aha/pdb
• Descriptor: Transmembrane protein gp41, (4S)-2-METHYL-2,4-PENTANEDIOL, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: coiled-coil, viral protein-inhibitor complex, membrane protein
• Biological source: Human immunodeficiency virus 1 (HIV-1); More
• Cellular location: Transmembrane protein gp41: Virion membrane; Single-pass type I membrane protein. Surface protein gp120: Virion membrane; Peripheral membrane protein: Q70626
• Total number of polymer chains: 6
• Total formula weight: 25684.88

Authors

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. (deposition date: 2010-04-22, release date: 2010-05-19, Last modification date: 2024-10-23)

Primary citation

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.
Characterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino terminal heptad repeat.
Antiviral Res., 2010

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.

PubMed: 20438763
DOI: 10.1016/j.antiviral.2010.04.011

Experimental method

X-RAY DIFFRACTION (1.7 Å)