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

Meytal Galilee; Akram Alian

Hindering the assembly of IN functional multimers is only one side of the coin. Allosteric interference has also been shown to promote the formation of aberrant IN multimers and aggregates. The potential of allosteric IN inhibitors has been demonstrated through the thorough characterization of the "LEDGF pocket" formed at the dimer interface of IN and the development of LEDGIN (or ALLINI) inhibitors that bind to it (11) (Figure 1A) . Although less investigated, other IN pockets capable of allosteric inhibitor binding have also been identified ( Figure 1A) : binding of the "Y3" molecule to a pocket near the N-terminal end of CCD α-helix 4, designated Y3pocket, has been shown to inhibit 3'-processing and strand-transfer activities (16) ; the "sucrose" binding pocket found along the CCD dimer interface and flanked by two LEDGF pockets (17, 18) has recently been targeted by the natural product kuwanon-L, which inhibited IN activity in a pattern similar to LEDGINs (19) . Another fragment-binding pocket "FBP" has also been identified at the CCD dimer interface (20) . Although inhibitory profiles for this FBP pocket have not been shown, our previous work on IN from the feline virus showed that a single Phe187Lys mutation (Phe185 in HIV-1 IN) around this site inhibits dimer formation (3) . Fragment-based screening and structural studies have revealed the capability of all three pockets (Y3, FBP and LEDGF) to bind numerous small molecules (21) . Most recently, a new class of LEDGINs has been shown to distinctively bind to undefined interfaces of both CCD and CTD of IN (22) . Therefore, IN harbors several allosteric hotspots that can be explored for novel anti-multimerization intervention strategies.