THE CATALYTIC DOMAIN OF HUMAN-IMMUNODEFICIENCY-VIRUS INTEGRASE - ORDERED ACTIVE-SITE IN THE F185H MUTANT

We solved the structure and traced the complete active site of the cat alytic domain of the human immunodeficiency virus type 1 integrase (HI V-1 IN) with the F185H mutation, The only previously available crystal structure, the F185K mutant of this domain, lacks one of the catalyti cally important residues, E152, located in a stretch of 12 disordered residues [Dyda et al, (1994) Science 266, 1981-1986], It is clear, how ever, that the active site of HIV-1 IN observed in either structure ca nnot correspond to that of the functional enzyme, since the cluster of three conserved carboxylic acids does not create a proper metal-bindi ng site. The conformation of the loop was compared with two different conformations found in the catalytic domain of the related avian sarco ma virus integrase [Bujacz et al. (1995) J. Mol. Biol. 253, 333-346]. Flexibility of the active site region of integrases may be required in order for the enzyme to assume a functional conformation in the prese nce of substrate and/or cofactors.