Structure-based modeling of the functional HIV-1 intasome and its inhibition

Krishnan, Lavanya, Li, Xiang, Naraharisetty, Hema L, Hare, Stephen, Cherepanov, Peter and Engelman, Alan (2010) Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 107 (36). pp. 15910-15915. ISSN 1091-6490

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The intasome is the basic recombination unit of retroviral integration, comprising the integrase protein and the ends of the viral DNA made by reverse transcription. Clinical inhibitors preferentially target the DNA-bound form of integrase as compared with the free protein, highlighting the critical requirement for detailed understanding of HIV-1 intasome structure and function. Although previous biochemical studies identified integrase residues that contact the DNA, structural details of protein–protein and protein–DNA interactions within the functional intasome were lacking. The recent crystal structure of the prototype foamy virus (PFV) integrase–viral DNA complex revealed numerous details of this related integration machine. Structures of drug-bound PFV intasomes moreover elucidated the mechanism of inhibitor action. Herein we present a model for the HIV-1 intasome assembled using the PFV structure as template. Our results pinpoint previously identified protein–DNA contacts within the quaternary structure and reveal hitherto unknown roles for Arg20 and Lys266 in DNA binding and integrase function. Models for clinical inhibitors bound at the HIV-1 integrase active site were also constructed and compared with previous studies. Our findings highlight the structural basis for HIV-1 integration and define the mechanism of its inhibition, which should help in formulating new drugs to inhibit viruses resistant to first-in-class compounds.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Stephen Hare
Date Deposited: 21 Sep 2017 14:58
Last Modified: 21 Sep 2017 14:58
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