HIV-1 capsid protein (CA) hexamer interface FG pocket (HIV-1 CA FG pocket)

The HIV-1 capsid protein (CA) hexamer interface FG pocket is a highly conserved hydrophobic site located at the junction of the N-terminal domain of one CA subunit and the C-terminal domain of an adjacent subunit within the hexameric lattice (PubMed: 32612211). This pocket is a critical functional hotspot that mediates the interaction between the viral capsid and essential host cell factors, including the nuclear pore protein NUP153 and the cleavage and polyadenylation specificity factor 6 (CPSF6) (PubMed: 24336210). These interactions are vital for the nuclear import of the viral pre-integration complex and the subsequent integration of viral DNA into the host genome. Therapeutic agents such as Lenacapavir (Sunlenca) target this pocket with picomolar affinity, effectively locking the capsid and disrupting multiple stages of the viral lifecycle, including assembly, uncoating, and nuclear transport (Nature, 2020, 583:114-118). Because the FG pocket is essential for viral fitness and is highly conserved across different HIV-1 strains, it represents a high-value target for long-acting antiretroviral therapies (NEJM, 2022, 386:1793-1803). The development of inhibitors for this site has provided a new treatment modality for patients with multi-drug resistant HIV-1 infection.

Other names

FG binding pocketCA-CA interface pocketPhenylalanine-glycine binding siteHIV-1 CA hexameric interfaceCapsid FG-binding site

Capsid inhibition via competitive binding at the FG pocket, which prevents interaction with host factors such as NUP153 and CPSF6, thereby disrupting capsid stability, uncoating, and nuclear transport (Nature, 2020, 583:114-118; PubMed: 32612211).