Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer

Youdong Mao, Liping Wang, Christopher Gu, Alon Herschhorn, Anik Désormeaux, Andrés Finzi, Shi-Hua Xiang, Joseph G. Sodroski

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer, a membrane-fusing machine, mediates virus entry into host cells and is the sole virus-specific target for neutralizing antibodies. Binding the receptors, CD4 and CCR5/CXCR4, triggers Env conformational changes fromthe metastable unliganded state to the fusion-active state. We used cryo-electron microscopy to obtain a 6-Å structure of the membrane-bound, heavily glycosylated HIV-1 Env trimer in its uncleaved and unliganded state. The spatial organization of secondary structure elements reveals that the unliganded conformations of both glycoprotein (gp)120 and gp41 subunits differ from those induced by receptor binding. The gp120 trimer association domains, which contribute to interprotomer contacts in the unliganded Env trimer, undergo rearrangement upon CD4 binding. In the unliganded Env, intersubunit interactions maintain the gp41 ectodomain helical bundles in a "spring-loaded" conformation distinct from the extended helical coils of the fusion-active state. Quaternary structure regulates the virus-neutralizing potency of antibodies targeting the conserved CD4-binding site on gp120. The Env trimer architecture provides mechanistic insights into the metastability of the unliganded state, receptor-induced conformational changes, and quaternary structure-based strategies for immune evasion.

Original languageEnglish (US)
Pages (from-to)12438-12443
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number30
DOIs
StatePublished - Jul 23 2013

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Neutralizing Antibodies
HIV-1
Glycoproteins
CCR5 Receptors
env Gene Products
Cryoelectron Microscopy
Immune Evasion
Virus Internalization
Viral Structures
CD4 Antigens
Membranes
Binding Sites
Viruses

Keywords

  • Cryo-EM
  • Membrane protein
  • Retrovirus
  • Spike
  • Vaccine immunogen

ASJC Scopus subject areas

  • General

Cite this

Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. / Mao, Youdong; Wang, Liping; Gu, Christopher; Herschhorn, Alon; Désormeaux, Anik; Finzi, Andrés; Xiang, Shi-Hua; Sodroski, Joseph G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 30, 23.07.2013, p. 12438-12443.

Research output: Contribution to journalArticle

Mao, Youdong ; Wang, Liping ; Gu, Christopher ; Herschhorn, Alon ; Désormeaux, Anik ; Finzi, Andrés ; Xiang, Shi-Hua ; Sodroski, Joseph G. / Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 30. pp. 12438-12443.
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