These authors contributed equally to the work.
Structural Basis of the Allosteric Inhibitor Interaction on the HIV-1 Reverse Transcriptase RNase H Domain
Article first published online: 31 AUG 2012
© 2012 John Wiley & Sons A/S
Chemical Biology & Drug Design
Volume 80, Issue 5, pages 706–716, November 2012
How to Cite
Christen, M. T., Menon, L., Myshakina, N. S., Ahn, J., Parniak, M. A. and Ishima, R. (2012), Structural Basis of the Allosteric Inhibitor Interaction on the HIV-1 Reverse Transcriptase RNase H Domain. Chemical Biology & Drug Design, 80: 706–716. doi: 10.1111/cbdd.12010
- Issue published online: 5 OCT 2012
- Article first published online: 31 AUG 2012
- Accepted manuscript online: 31 JUL 2012 02:55AM EST
- Received 8 March 2012, revised 22 June 2012 and accepted for publication 17 July 2012
- molecular docking;
- reverse transcriptase;
- ribonuclease H
HIV-1 reverse transcriptase (RT) has been an attractive target for the development of antiretroviral agents. Although this enzyme is bi-functional, having both DNA polymerase and ribonuclease H (RNH) activities, there is no clinically approved inhibitor of the RNH activity. Here, we characterize the structural basis and molecular interaction of an allosteric site inhibitor, BHMP07, with the wild-type (WT) RNH fragment. Solution NMR experiments for inhibitor titration on WT RNH showed relatively wide chemical shift perturbations, suggesting a long-range conformational effect on the inhibitor interaction. Comparisons of the inhibitor-induced NMR chemical shift changes of RNH with those of RNH dimer, in the presence and absence of Mg2+, were performed to determine and verify the interaction site. The NMR results, with assistance of molecular docking, indicate that BHMP07 preferentially binds to a site that is located between the RNH active site and the region encompassing helices B and D (the ‘substrate-handle region’). The interaction site is consistent with the previous proposed site, identified using a chimeric RNH (p15-EC) [Gong et al. (2011) Chem Biol Drug Des 77, 39–47], but with slight differences that reflect the characteristics of the amino acid sequences in p15-EC compared to the WT RNH.