title: Molecular architecture of native HIV-1 gp120 trimers.
abstract: The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartesaghi
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Borgnia
authors.forename: Guillermo
authors.initials: G
authors.lastname: Sapiro
authors.forename: Sriram
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism; D020285:Cryoelectron Microscopy; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry*; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D021122:Protein Subunits