title: A homology model of HIV-1 integrase and analysis of mutations designed to test the model.
abstract: Although there are structures of the different domains of human immunodeficiency virus type 1 (HIV-1) integrase (IN), there is no structure of the entire protein. The recently determined crystal structures of the prototype foamy virus (PFV) IN tetramer, in complexes with viral DNA, led to the generation of models of full-length HIV-1 IN. These models were generated, in part, by superimposing the structures of the domains of HIV-1 IN onto the structure of full-length PFV IN. We developed a model for HIV-1 IN-based solely on its sequence alignment with PFV IN-that differs in several ways from the previous models. Specifically, in our model, the junction between the catalytic core domain and C-terminal domain adopts a helix-loop-helix motif that is similar to the corresponding segment of PFV IN and differs from the crystal structures of these two HIV-1 IN domains. The alignment of residues in the C-terminal domain also differs from the previous models. Our model can be used to explain the phenotype of previously published HIV-1 IN mutants. We made additional mutants, and the behavior of these new mutants provides additional support for the model.
authors.affiliation: HIV Drug Resistance Program, Center for Cancer Research, National Cancer Institute, P.O. Box B, Frederick, MD 21702, USA. barryj2@mail.nih.gov
authors.forename: Barry C
authors.initials: BC
authors.lastname: Johnson
authors.forename: Mathieu
authors.initials: M
authors.lastname: Métifiot
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferris
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
mesh_terms: D000595:Amino Acid Sequence; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011487:Protein Conformation; D016415:Sequence Alignment; D016092:Spumavirus / Q000737:chemistry / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
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