Crystal structures of catalytic core domains of retroviral integrases and role of divalent cations in enzymatic activity.

Crystal structures of the enzymatically competent catalytic domains of HIV-1 and ASV IN have been solved in the last few years. The structure of HIV-1 IN has been described only for apoenzyme and for a complex with Mg2+, whereas the structure of ASV IN has been presented as the apoenzyme, in the presence of divalent cations (Mn2+, Mg2+, Ca2+, Zn2+, and Cd2+), and with an inhibitor. A single ion of Mn2+, Mg2+, or Ca2+ interacts with the two aspartate side chains of the D,D(35)E catalytic center in octahedral coordination with four water molecules. However, two ions of Zn2+ or Cd2+ bind to the active site of IN with tetrahedral and octahedral coordination, respectively. Only small adjustments take place in the active site of ASV IN on binding of the metal cofactor(s), which are absolutely required for the activity of this enzyme. The placement of the side chains and metal ions in the active site is very similar to that observed even in distant members of this superfamily of polynucleotidyltransferases. Here the role of divalent cations in the enzymatic activity of IN and the search for inhibitors of this enzyme are discussed.