1. Microbiology and Infectious Disease
  2. Structural Biology and Molecular Biophysics

HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations

  1. Xiaochu Ma
  2. Maolin Lu
  3. Jason Gorman
  4. Daniel S Terry
  5. Xinyu Hong
  6. Zhou Zhou
  7. Hong Zhao
  8. Roger B Altman
  9. James Arthos
  10. Scott C Blanchard
  11. Peter D Kwong
  12. James B Munro  Is a corresponding author
  13. Walther Mothes  Is a corresponding author
  1. Yale University School of Medicine, United States
  2. National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States
  3. Weill Cornell Medical College of Cornell University, United States
  4. Tufts University School of Medicine, United States
https://doi.org/10.7554/eLife.34271
Share this article
Cite this article
  1. Xiaochu Ma
  2. Maolin Lu
  3. Jason Gorman
  4. Daniel S Terry
  5. Xinyu Hong
  6. Zhou Zhou
  7. Hong Zhao
  8. Roger B Altman
  9. James Arthos
  10. Scott C Blanchard
  11. Peter D Kwong
  12. James B Munro
  13. Walther Mothes
(2018)
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations
eLife 7:e34271.
https://doi.org/10.7554/eLife.34271
  2. Download BibTeX
  3. Download .RIS

Abstract

HIV-1 entry into cells requires binding of the viral envelope glycoprotein (Env) to receptor CD4 and coreceptor. Imaging of individual Env molecules on native virions shows Env trimers to be dynamic, spontaneously transitioning between three distinct well-populated conformational states: a pre-triggered Env (State 1), a default intermediate (State 2) and a three-CD4-bound conformation (State 3), which can be stabilized by binding of CD4 and coreceptor-surrogate antibody 17b. Here, using single-molecule Fluorescence Resonance Energy Transfer (smFRET), we show the default intermediate configuration to be asymmetric, with individual protomers adopting distinct conformations. During entry, this asymmetric intermediate forms when a single CD4 molecule engages the trimer. The trimer can then transition to State 3 by binding additional CD4 molecules and coreceptor.

Article and author information

Author details

  1. Xiaochu Ma

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.

  2. Maolin Lu

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.

  3. Jason Gorman

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.

  4. Daniel S Terry

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.

  5. Xinyu Hong

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.

  6. Zhou Zhou

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.

  7. Hong Zhao

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.

  8. Roger B Altman

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.

  9. James Arthos

    Immunopathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.

  10. Scott C Blanchard

    Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2717-9365

  11. Peter D Kwong

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
    Competing interests
    No competing interests declared.

  12. James B Munro

    Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, United States
    For correspondence
    james.munro@tufts.edu
    Competing interests
    No competing interests declared.

  13. Walther Mothes

    Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, United States
    For correspondence
    walther.mothes@yale.edu
    Competing interests
    Walther Mothes, Patent applications pertaining to this work are U.S. Patent Application 13/202,351, Methods and Compositions for Altering Photophysical Properties of Fluorophores via Proximal Quenching (S.C.B., Z.Z.); U.S. Patent Application 14/373,402 Dye Compositions, Methods of Preparation, Conjugates Thereof, and Methods of Use (S.C.B., Z.Z.); and International and US Patent Application PCT/US13/42249 Reagents and Methods for Identifying Anti-HIV Compounds (S.C.B., J.B.M., W.M.). S.C.B. is a co-founder of Lumidyne Corporation.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3367-7240

Funding

National Institutes of Health (GM116654)

  • Walther Mothes

National Institutes of Health (AI116262)

  • James B Munro

National Institutes of Health (GM098859)

  • Scott C Blanchard

National Institutes of Health (GM056550)

  • Scott C Blanchard
  • Walther Mothes

Cancer Research Institute (Irvington Fellows Program)

  • James B Munro

National Institutes of Health (AI042853)

  • James B Munro

China Scholarship Council (Yale World Scholars)

  • Xiaochu Ma

National Institutes of Health (GM103310)

  • Peter D Kwong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 3,426
    views
  • 618
    downloads
  • 141
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiaochu Ma
  2. Maolin Lu
  3. Jason Gorman
  4. Daniel S Terry
  5. Xinyu Hong
  6. Zhou Zhou
  7. Hong Zhao
  8. Roger B Altman
  9. James Arthos
  10. Scott C Blanchard
  11. Peter D Kwong
  12. James B Munro
  13. Walther Mothes
(2018)
HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations
eLife 7:e34271.
https://doi.org/10.7554/eLife.34271

Share this article

https://doi.org/10.7554/eLife.34271

Categories and tags

Research organism