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PMID: 10482611 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core: role of a conserved hydrophobic cavity in membrane fusion.

Journal of virology ·Vol. 73 ·No. 10 ·1999-10-00 ·Pages 8578-86

Ji H, Shu W, Burling FT, Jiang S, Lu M

Abstract

The gp41 envelope protein of human immunodeficiency virus type 1 (HIV-1) contains an alpha-helical core structure responsible for mediating membrane fusion during viral entry. Recent studies suggest that a conserved hydrophobic cavity in the coiled coil of this core plays a distinctive structural role in maintaining the fusogenic conformation of the gp41 molecule. Here we investigated the importance of this cavity in determining the structure and biological activity of the gp41 core by using the N34(L6)C28 model. The high-resolution crystal structures of N34(L6)C28 of two HIV-1 gp41 fusion-defective mutants reveal that each mutant sequence is accommodated in the six-helix bundle structure by forming the cavity with different sets of atoms. Remarkably, the mutant N34(L6)C28 cores are highly effective inhibitors of HIV-1 infection, with 5- to 16-fold greater activity than the wild-type molecule. The enhanced inhibitory activity by fusion-defective mutations correlates with local structural perturbations close to the cavity that destabilize the six-helix bundle. Taken together, these results indicate that the conserved hydrophobic coiled-coil cavity in the gp41 core is critical for HIV-1 entry and its inhibition and provides a potential antiviral drug target.

MeSH Terms
Amino Acid Sequence Cell Membrane/physiology,ultrastructure HIV Envelope Protein gp41/physiology HIV Infections/pathology,virology HIV-1/physiology,ultrastructure Humans Membrane Fusion Molecular Sequence Data Protein Binding Virus Replication
Chemicals
HIV Envelope Protein gp41
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ji H
Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.
Shu W
Burling F T
Jiang S
Lu M
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.73.10.8578-8586.1999
Published
1999-10-00
Pages
8578-86
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC112878
Subset
IM
Grants
NIAID NIH HHS · R01 AI042382 · United States
NIAID NIH HHS · R56 AI042382 · United States
NIAID NIH HHS · AI-42382 · United States
NIAID NIH HHS · AI-42693 · United States
External Links
PubMed source DOI: 10.1128/JVI.73.10.8578-8586.1999 PMC Full Text View journal details
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