5HFL

Gp41-targeting HIV-1 fusion inhibitors with helical Ile-Asp-Leu tail

Summary for 5HFL

• Entry DOI: 10.2210/pdb5hfl/pdb
• Related: 5HFM
• Descriptor: Envelope glycoprotein,gp41 CHR region (2 entities in total)
• Functional Keywords: hiv-1, fusion inhibitor, ile-asp-leu tail, helical tail, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 6
• Total formula weight: 51821.21

Authors

Zhu, Y.,Ye, S.,Zhang, R. (deposition date: 2016-01-07, release date: 2017-01-11, Last modification date: 2024-03-20)

Primary citation

Zhu, Y.,Su, S.,Qin, L.,Wang, Q.,Shi, L.,Ma, Z.,Tang, J.,Jiang, S.,Lu, L.,Ye, S.,Zhang, R.
Rational improvement of gp41-targeting HIV-1 fusion inhibitors: an innovatively designed Ile-Asp-Leu tail with alternative conformations
Sci Rep, 6:31983-31983, 2016

PubMed Abstract: Peptides derived from the C-terminal heptad repeat (CHR) of HIV gp41 have been developed as effective fusion inhibitors against HIV-1, but facing the challenges of enhancing potency and stability. Here, we report a rationally designed novel HIV-1 fusion inhibitor derived from CHR-derived peptide (Trp628~Gln653, named CP), but with an innovative Ile-Asp-Leu tail (IDL) that dramatically increased the inhibitory activity by up to 100 folds. We also determined the crystal structures of artificial fusion peptides N36- and N43-L6-CP-IDL. Although the overall structures of both fusion peptides share the canonical six-helix bundle (6-HB) configuration, their IDL tails adopt two different conformations: a one-turn helix with the N36, and a hook-like structure with the longer N43. Structural comparison showed that the hook-like IDL tail possesses a larger interaction interface with NHR than the helical one. Further molecular dynamics simulations of the two 6-HBs and isolated CP-IDL peptides suggested that hook-like form of IDL tail can be stabilized by its binding to NHR trimer. Therefore, CP-IDL has potential for further development as a new HIV fusion inhibitor, and this strategy could be widely used in developing artificial fusion inhibitors against HIV and other enveloped viruses.

PubMed: 27666394
DOI: 10.1038/srep31983

Experimental method

X-RAY DIFFRACTION (2.294 Å)