![]() ![]() ![]() Both spontaneous and CD4-induced transitions of virion Env conformations have been characterized by single-molecule fluorescence resonance energy transfer (smFRET) 5. ![]() The resulting mature Env, which consists of a gp120 exterior subunit and a gp41 transmembrane subunit in each of the three protomers, is incorporated into budding virions.ĭuring virus entry, gp120 engages the target cell receptors, CD4 and CCR5 (or CXCR4), and gp41 fuses the viral and cell membranes 1, 2. During transport through the Golgi apparatus, a subset of the Env glycans are modified to complex carbohydrates and the Env precursor is cleaved by host furin-like proteases 3, 4. In infected cells, Env is synthesized as a gp160 precursor in the endoplasmic reticulum, where trimerization, disulfide bonding and the addition of high-mannose glycans occur 3, 4. The entry of human immunodeficiency virus type-1 (HIV-1), the etiologic agent of AIDS, into host cells is mediated by the envelope glycoprotein (Env) trimer 1, 2. The broken symmetry of the DIS potentially assists Env binding to two CD4 receptors-while resisting antibody binding-and promotes extension of the gp41 HR1 helical coiled-coil, which relocates the fusion peptide closer to the target cell membrane. Breaking conformational symmetry is allosterically coupled with dynamic helical transformations of the gp41 N-terminal heptad repeat (HR1 N) regions in two protomers and with trimer tilting in the membrane. Cleaved and uncleaved Env trimers assumed remarkably consistent yet distinct asymmetric conformations, with one smaller and two larger opening angles. The cleaved Env trimers exhibited tighter subunit packing than uncleaved trimers. Here, we present cryo-EM structures at near-atomic resolution of two cleaved full-length HIV-1 Env trimers purified from cell membranes in styrene-maleic acid lipid nanoparticles without antibodies or receptors. During virus entry, the pretriggered human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer initially transits into a default intermediate state (DIS) that remains structurally uncharacterized. ![]()
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