CD4 binding site on HIV-1 envelope glycoprotein gp120 (CD4bs)

The CD4 binding site on HIV-1 envelope glycoprotein gp120 is a recessed pocket, often called the Phe43 cavity, located at the interface between the inner and outer domains of gp120. It serves as the primary interaction site for the CD4 receptor on host cells, where CD4's Phe43 residue inserts to trigger major conformational changes in gp120, forming a bridging sheet and exposing the coreceptor-binding site (CCR5 or CXCR4) essential for viral entry. These changes initiate the fusion of viral and cell membranes via gp41 rearrangements but are restrained in the unliganded state by variable loops (V1/V2, V3) and gp41 interactions to prevent premature activation. The site is highly conserved across HIV-1 clades yet recessed for immune evasion, making it challenging for antibodies while attractive for therapeutics like CD4 mimetics (e.g., NBD-556, MCG-IV-210) that bind the cavity to lock gp120 in the CD4-bound conformation, enhancing neutralization. Structural studies of unliganded and liganded gp120 cores show the CD4-bound state as a "ground state" for the core, with inner domain layers modulating cavity shape and sensitivity. Targeting this site risks functional inactivation due to gp120 shedding or altered spike stability.

Other names

CD4-binding sitePhe43 cavityCD4bs pocket

Mimics CD4 to bind Phe43 cavity and induce CD4-bound conformation, Stabilizes gp120 in CD4-bound state for neutralization or entry inhibition