title: Quaternary structures of HIV Env immunogen exhibit conformational vicissitudes and interface diminution elicited by ligand binding.
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.
authors: Department of Molecular and Cellular Biology, University of California, Davis, CA 95616, USA.
authors: Carlos G
authors: CG
authors: Moscoso
authors: Yide
authors: Y
authors: Sun
authors: Selina
authors: S
authors: Poon
authors: Li
authors: L
authors: Xing
authors: Elaine
authors: E
authors: Kan
authors: Loïc
authors: L
authors: Martin
authors: Dominik
authors: D
authors: Green
authors: Frank
authors: F
authors: Lin
authors: Anders G
authors: AG
authors: Vahlne
authors: Susan
authors: S
authors: Barnett
authors: Indresh
authors: I
authors: Srivastava
authors: R Holland
authors: RH
authors: Cheng
mesh_terms: D015704:CD4 Antigens / Q000276:immunology; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D016056:Immunodominant Epitopes; D008024:Ligands; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1