Author ORCID Identifier
Document Type
Article
Publication Date
7-30-2010
Abstract
Human immunodeficiency virus, type 1 (HIV-1) envelope glycoprotein (gp120/gp41) plays a critical role in virus infection and pathogenesis. Three of the six monoclonal antibodies considered to have broadly neutralizing activities (2F5, 4E10, and Z13e1) bind to the membrane-proximal external region (MPER) of gp41. This makes the MPER a desirable template for developing immunogens that can elicit antibodies with properties similar to these monoclonal antibodies, with a long term goal of developing antigens that could serve as novel HIV vaccines. In order to provide a structural basis for rational antigen design, an MPER construct, HR1-54Q, was generated for x-ray crystallographic and x-ray footprinting studies to provide both high resolution atomic coordinates and verification of the solution state of the antigen, respectively. The crystal structure of HR1-54Q reveals a trimeric, coiled-coil six-helical bundle, which probably represents a postfusion form of gp41. The MPER portion extends from HR2 in continuation of a slightly bent long helix and is relatively flexible. The structures observed for the 2F5 and 4E10 epitopes agree well with existing structural data, and enzyme-linked immunosorbent assays indicate that the antigen binds well to antibodies that recognize the above epitopes. Hydroxyl radical-mediated protein footprinting of the antigen in solution reveals specifically protected and accessible regions consistent with the predictions based on the trimeric structure from the crystallographic data. Overall, the HR1-54Q antigen, as characterized by crystallography and footprinting, represents a postfusion, trimeric form of HIV gp41, and its structure provides a rational basis for gp41 antigen design suitable for HIV vaccine development.
Keywords
antigen, glycoprotein, HIV, protein structure, x-ray crystallography, x-ray footprinting, vaccine design
Publication Title
Journal of Biological Chemistry
Volume
285
Issue
31
First Page
24290
Last Page
24298
Rights
© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Wuxian Shi, Jen Bohon, Dong P. Han, Habtom Habte, Yali Qin, Michael W. Cho, Mark R. Chance. Structural Characterization of HIV gp41 with the Membrane-proximal External Region. Journal of Biological Chemistry, Volume 285, Issue 31, 2010, Pages 24290-24298, https://doi.org/10.1074/jbc.M110.111351.