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Complexes of HIV‐1 integrase with HAT proteins: Multiscale models, dynamics, and hypotheses on allosteric sites of inhibition
Author(s) -
Di Fenza Armida,
Rocchia Walter,
Tozzini Valentina
Publication year - 2009
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22399
Subject(s) - integrase , allosteric regulation , acetyltransferases , molecular dynamics , mutagenesis , computational biology , drug discovery , human immunodeficiency virus (hiv) , chemistry , protein structure , biology , computational chemistry , enzyme , acetylation , biochemistry , mutation , virology , gene
A new and very promising strategy for HIV drug discovery consists in blocking the multiple functional interactions between HIV‐1 integrase (IN) and its cellular cofactors. At present, this line of action is hindered by the absence of three‐dimensional structures of IN in complex with any of them. In this article, we developed a full‐length three‐dimensional structure of IN, including the highly flexible terminal residues 270–288, which are not experimentally solved. Additionally, we built models of IN complexed to the human acetyltransferases GCN5 and p300 based on available structural and mutagenesis data. Then, we studied the dynamical behavior of these models by means of the Coarse‐Grained Molecular Dynamics (CGMD) and Essential Dynamics (ED) to locate and characterize the nature of the largest collective motions. We found correlated motions involving distant regions of IN. Moreover, we found that these are influenced by the binding with the acetyltransferases (HATs). Taken together these findings suggest a way to affect the acetyltransferase binding by an allosteric type of inhibition and provide an important new approach for the drug design against HIV disease. Proteins 2009. © 2009 Wiley‐Liss, Inc.