A three-dimensional model of the human immunodeficiency virus type 1 integration complex.
While the general features of HIV-1 integrase function are understood, there is still uncertainty about the composition of the integration complex and how integrase interacts with viral and host DNA. We propose an improved model of the integration complex based on current experimental evidence including a comparison with the homologous Tn5 transposase containing bound DNA and an analysis of DNA binding sites using Goodford's GRID. Our model comprises a pair of integrase dimers, two strands of DNA to represent the viral DNA ends and a strand of bent DNA representing the host chromosome. In our model, the terminal four base pairs of each of the viral DNA strands interact with the integrase dimer providing the active site, while bases one turn away interact with a flexible loop (residues 186-194) on the second integrase dimer. We propose that residues E152, Q148 and K156 are involved in the specific recognition of the conserved CA dinucleotide and that the active site mobile loop (residues 140-149) stabilises the integration complex by acting as a barrier to separate the two viral DNA ends. In addition, the residues responsible for DNA binding in our model show a high level of amino acid conservation.
Wielens
Jerome
J
Department of Medicinal Chemistry, Monash University, 381 Royal Parade, 3052, Parkville, Vic., Australia. jerome.wielens@vcp.monash.edu.au
Crosby
Ian T
IT
Chalmers
David K
DK
D000595:Amino Acid Sequence; D001483:Base Sequence; D003198:Computer Simulation; D017124:Conserved Sequence; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D019281:Dimerization; D015658:HIV Infections / Q000235:genetics / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016662:Virus Integration
D004279:DNA, Viral; D046911:Macromolecular Substances; D019427:HIV Integrase