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A Homology Model of HIV-1 Integrase and Analysis of Mutations Designed to Test the Model

Author:
Johnson, Barry C., Métifiot, Mathieu, Ferris, Andrea, Pommier, Yves, Hughes, Stephen H.
Source:
Journal of Molecular Biology 2013 v.425 pp. 2133-2146
ISSN:
0022-2836
Subject:
DNA, Human immunodeficiency virus 1, crystal structure, models, mutants, mutation, phenotype, sequence alignment, viruses
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.
Agid:
1021854