Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding: Role of DNA backbone flexibility and an open catalytic site

Allison A. Johnson, Jane M. Sayer, Haruhiko Yagi, Sachindra S. Patil, Françoise Debart, Martin A. Maier, David R. Corey, Jean Jacques Vasseur, Terrence R. Burke, Victor E. Marquez, Donald M. Jerina, Yves Pommier

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Integration of the viral cDNA into host chromosomes is required for viral replication. Human immunodeficiency virus integrase catalyzes two sequential reactions, 3′-processing (3′-P) and strand transfer (ST). The first integrase inhibitors are undergoing clinical trial, but interactions of inhibitors with integrase and DNA are not well understood in the absence of a co-crystal structure. To increase our understanding of integrase interactions with DNA, we examined integrase catalysis with oligonucleotides containing DNA backbone, base, and groove modifications placed at unique positions surrounding the 3′-processing site. 3′-Processing was blocked with substrates containing constrained sugars and α-anomeric residues, suggesting that integrase requires flexibility of the phosphodiester backbone at the 3′-P site. Of several benzo[a]pyrene 7,8-diol 9,10-epoxide (BaP DE) adducts tested, only the adduct in the minor groove at the 3′-P site inhibited 3′-P, suggesting the importance of the minor groove contacts for 3′-P. ST occurred in the presence of bulky BaP DE DNA adducts attached to the end of the viral DNA suggesting opening of the active site for ST. Position-specific effects of these BaP DE DNA adducts were found for inhibition of integrase by diketo acids. Together, these results demonstrate the importance of DNA structure and specific contacts with the viral DNA processing site for inhibition by integrase inhibitors.

Original languageEnglish (US)
Pages (from-to)32428-32438
Number of pages11
JournalJournal of Biological Chemistry
Volume281
Issue number43
DOIs
StatePublished - Oct 27 2006

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HIV Integrase Inhibitors
Integrase Inhibitors
Integrases
Catalytic Domain
DNA
Processing
Viral DNA
DNA Adducts
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Virus Integration
Catalysis
Oligonucleotides
Chromosomes
Viruses
Sugars
Complementary DNA
p31 integrase protein, Human immunodeficiency virus 1
Clinical Trials
HIV
Crystal structure

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding : Role of DNA backbone flexibility and an open catalytic site. / Johnson, Allison A.; Sayer, Jane M.; Yagi, Haruhiko; Patil, Sachindra S.; Debart, Françoise; Maier, Martin A.; Corey, David R.; Vasseur, Jean Jacques; Burke, Terrence R.; Marquez, Victor E.; Jerina, Donald M.; Pommier, Yves.

In: Journal of Biological Chemistry, Vol. 281, No. 43, 27.10.2006, p. 32428-32438.

Research output: Contribution to journalArticle

Johnson, AA, Sayer, JM, Yagi, H, Patil, SS, Debart, F, Maier, MA, Corey, DR, Vasseur, JJ, Burke, TR, Marquez, VE, Jerina, DM & Pommier, Y 2006, 'Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding: Role of DNA backbone flexibility and an open catalytic site', Journal of Biological Chemistry, vol. 281, no. 43, pp. 32428-32438. https://doi.org/10.1074/jbc.M605101200
Johnson, Allison A. ; Sayer, Jane M. ; Yagi, Haruhiko ; Patil, Sachindra S. ; Debart, Françoise ; Maier, Martin A. ; Corey, David R. ; Vasseur, Jean Jacques ; Burke, Terrence R. ; Marquez, Victor E. ; Jerina, Donald M. ; Pommier, Yves. / Effect of DNA modifications on DNA processing by HIV-1 integrase and inhibitor binding : Role of DNA backbone flexibility and an open catalytic site. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 43. pp. 32428-32438.
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