Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding

Carlos G. Moscoso, Yide Sun, Selina Poon, Li Xing, Elaine Kan, Loïc Martin, Dominik Green, Frank Lin, Anders G. Vahlne, Susan Barnett, Indresh Srivastava, R. Holland Cheng

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Abstract

The human immunodeficiency virus envelope protein is the key element mediating entry into host cells. Conformational rearrangement of Env upon binding to the host CD4 receptor and chemokine coreceptor drives membrane fusion. We elucidated the quaternary arrangement of the soluble Env trimeric immunogen o-gp140δV2TV1, in both its native (unliganded) and CD4-induced (liganded) states by cryoelectron microscopy and molecular modeling. The liganded conformation was elicited by binding gp140 to the synthetic CD4-mimicking miniprotein CD4m. Upon CD4m binding, an outward domain shift of the three gp120 subunits diminishes gp120-gp41 interactions, whereas a "flat open" concave trimer apex is observed consequent to gp120 tilting away from threefold axis, likely juxtaposing the fusion peptide with the host membrane. Additional features observed in the liganded conformation include rotations of individual gp120 subunits that may release gp41 for N- and C-helix refolding and also may lead to optimal exposure of the elicited coreceptor binding site. Such quaternary arrangements of gp140 lead to the metastable liganded conformation, with putative locations of exposed epitopes contributing to a description of sequential events occurring prior to membrane fusion. Our observations imply a mechanism whereby a soluble Env trimeric construct, as opposed to trimers extracted from virions, may better expose crucial epitopes such as the CD4 binding site and V3, as well as epitopes in the vicinity of gp41, subsequent to conjugation with CD4m. Structural features gleaned from our studies should aid the design of Env-based immunogens for inducement of potent broadly neutralizing antibodies against exposed conformational epitopes.

Original languageEnglish (US)
Pages (from-to)6091-6096
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number15
DOIs
StatePublished - Apr 12 2011

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Moscoso, C. G., Sun, Y., Poon, S., Xing, L., Kan, E., Martin, L., Green, D., Lin, F., Vahlne, A. G., Barnett, S., Srivastava, I., & Cheng, R. H. (2011). Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding. Proceedings of the National Academy of Sciences of the United States of America, 108(15), 6091-6096. https://doi.org/10.1073/pnas.1016113108