Multimerization of HIV-1 integrase hinges on conserved SH3-docking platforms

Meytal Galilee; Akram Alian

Multimerization of HIV-1 IN depends on the delicate compatibility of amino acids lining the interacting interfaces (9), providing an attractive targeting strategy. Interfering with the interacting domains can be exploited not only to promote aberrant multimerization but also to inhibit the assembly of functional multimers, an opportunity offered by the CCD/NTD (HTH-cleft) (9) and the CCD/CTD (SH3-cleft) docking platform reported here. The SH3-cleft (site-2) relates to a previously identified "Y3" pocket observed almost two decades ago in a crystal structure of retroviral IN CCD bound to the small molecule (Y3) ( Figure 1A) , which efficiently inhibits IN catalytic activity (16) . A recent fragment-based screening study has also captured several other small molecules bound near this site (21) (Figure 1A, CDQ) , however, the inhibitory profiles where not characterized.