One of the three subunits of the HIV-1 Env gp trimer is depicted, oriented so that the viral membrane is at the top of the figure. The gp41 ectodomain is colored orange, the gp120 N and C termini cyan, the β-sandwich red, Layer 1 magenta, Layer 2 green, Layer 3 yellow, outer domain (OD) yellow, and the β20-β21 loop blue. In the unliganded state (left figure), Layer 1 and Layer 2 assume conformations different from that observed in the CD4-bound state (Pancera et al., 2010), allowing both layers to interact with the gp41 ectodomain. CD4 binding results in the apposition of Layer 1 and Layer 2 (right figure). This rearrangement of the gp120 inner domain slows the off-rate of CD4 and allows the gp41 ectodomain to undergo additional conformational changes necessary for HIV-1 entry.