THE CRYSTAL STRUCTURE OF THE CATALYTIC CORE DOMAIN OF HIV-1 INTEGRASE IN A NEW CRYSTAL FORM. Fred Dyda, Alison B. Hickman, Timothy M. Jenkins, Alan Engelman, Robert Craigie, David R. Davies. Laboratory of Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases

The catalytic core domain of HIV-1 integrase has been crystallized in the orthorhombic space group P2₁2₁2₁ with two molecules in the asymmetric unit. The structure was solved by molecular replacement. When compared with the previously reported trigonal form (Dyda et. al. Science 266, pp1981-1986, 1994), this orthorhombic form diffracts to higher resolution, and previously undefined parts of the structure now became ordered, probably due to the different crystal packing environment. The full active site consisting of three acidic residues is well resolved in this crystal form.

A detailed three dimensional comparison of the members of the polynucleotidyl transferase superfamily (HIV-1 integrase, Mu transposase, RNase H, RuvC resolvase, ASV integrase) shows that the closest similarity is between the integrases and the Mu transposase. This surprisingly close similarity correlates with the similarity of the chemical reactions these enzymes catalyze. When considering the entire superfamily, it is interesting to observe that the molecules display a similar disorder pattern. This is especially true in the active site region, where the location of the catalytically essential carboxylate residues varies significantly even between the two integrases. This probably indicates a conformational rearrangement taking place upon the formation of the protein-DNA complex prior to catalysis.