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

Meytal Galilee; Akram Alian

The inability of peptide to bind CCDCTD, which possesses an exposed site-1 but blocked site-2, indicates that site-2, which docks the CTD during multimerization, is a preferred binding site. CTD involvement in the multimerization of IN is well documented (reviewed in (23)), and the relative orientation of the CTD with regard to the CCD has previously been implicated in functional IN assembly (29) . Moreover, analysis of available CCD structures bound to small molecules at site-2 reveals a pocket that forms upon binding, which displaces the flexible N-terminus of α4, a displacement that would also interfere with and inhibit the binding of viral DNA and IN catalytic activity ( Figure 4D ). Therefore, we propose site-2 for future structure based design or screening of small molecules that can interfere with CCD/CTD interactions during IN multimerization, and can promote the formation of a binding pocket that would also inactivate the catalytic site by displacing α4 into an aberrant configuration.