Integrase, metal binding site

A in the CITEP crystal structure. These are essentially the same, due to the resolution of the experimental structure. These n interactions are not optimal. Our optimizations of metal ion ti complexes with both the thiazolothiazepines and the salicylhydrazines result in distances of less than 3 A. The apparent weakness of this interaction may demonstrate why our studies of inhibitor complexes with metal ions did not support a direct metal ion interaction. Studies are under way to dock the CITEP inhibitor to the integrase catalytic core to evaluate whether the scoring methods used to rank the salicylhydrazine complexes are able to accurately provide a consensus that the metal ion site is more favorable for this inhibitor. The result of this evaluation will determine whether our apparent consensus favoring the site above the catalytic loop for the salicylhydrazines does indeed represent the preferred binding site for this class of inhibitors. 

Several tetrahedral cuprous phenanthroline complexes, known inhibitors of transcription, were tested against integrase and shown to be reasonably effective inhibitors [56] IC50 values in the range of 1-10 jiMwere determined (for example, the neocuproine-Cu+ complex, XII). Analyses of the mode of inhibition demonstrated that these compounds act noncompetitively, and that inhibition does not correlate with inhibition of DNA binding. Thus, it has been proposed that these metal chelates may act at a site distant from the active site, or perhaps in the context of an enzyme-DNA complex. 

It may be possible to inhibit integrase by preventing the binding of the required metal cofactor(s) to the active site acidic residues that are presumed to provide... 

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