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

Meytal Galilee; Akram Alian

To demonstrate the ability of a fragment specific to site-2 to interfere with CCD/CTD docking and consequently inhibit IN multimerization, we evaluated the inhibitory effects of the Y3-molecule, which specifically binds at site-2 (16) . Indeed, using chemical crosslinking we show that the Y3-molecule attenuates IN . CC-BY 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/301721 doi: bioRxiv preprint multimerization in a dose-dependent manner ( Figure 2F ), corroborating on the potentials of a site-2 bound peptide to inhibit IN multimerizaion. Therefore, peptide binding at either of these sites, or both, would inhibit CTD interactions with CCD, and can rationalize the observed inhibition of IN multimerization ( Figure 1E ) and strand-transfer activity ( Figure 1D ). It is worth noting that since both docking sites involve not only the CTD but also the NTD linker segment (residues 50-58) ( Figure 2B ), peptide binding would also interfere with the vital docking of NTDs during IN multimerization.