Figure 7. A model illustrating how inhibition of CUL5 NEDD8ylation leads to reduced infectivity of HIV.

Two enzymatic steps must take place in order for CRL5^Vif-CBFß to be properly activated by NEDD8 conjugation, and therefore for A3G-degradation to take place, in cells infected with HIV. First, NEDD8 is loaded onto the E2 UBE2F by NAE. The small molecule MLN4924 is able to inhibit this step, blocking degradation of A3G and thereby reducing viral infectivity. Second, UBE2F is recognized by the RBX2 subunit of CRL5^Vif-CBFß, and transfers NEDD8 to CUL5.