Structural basis of HIV-1 resistance to AZT by excision

Xiongying Tu, Kalyan Das, Qianwei Han, Joseph D. Bauman, Arthur D. Clark, Xiaorong Hou, Yulia V. Frenkel, Barbara L. Gaffney, Roger A. Jones, Paul L. Boyer, Stephen H. Hughes, Stefan G. Sarafianos, Eddy Arnold

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Human immunodeficiency virus (HIV-1) develops resistance to 3′-azido-2′,3′-deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of AZT monophosphate from the 3′ end of the primer. The excision reaction occurs at the dNTP-binding site, uses ATP as a pyrophosphate donor, unblocks the primer terminus and allows reverse transcriptase to continue viral DNA synthesis. The excision product is AZT adenosine dinucleoside tetraphosphate (AZTppppA). We determined five crystal structures: wild-type reverse transcriptase-double-stranded DNA (RT-dsDNA)-AZTppppA; AZT-resistant (AZTr; M41L D67N K70R T215Y K219Q) RT-dsDNA-AZTppppA; AZTr RT-dsDNA terminated with AZT at dNTP-and primer-binding sites; and AZTr apo reverse transcriptase. The AMP part of AZTppppA bound differently to wild-type and AZTr reverse transcriptases, whereas the AZT triphosphate part bound the two enzymes similarly. Thus, the resistance mutations create a high-affinity ATP-binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision.

Original languageEnglish (US)
Pages (from-to)1202-1209
Number of pages8
JournalNature Structural and Molecular Biology
Volume17
Issue number10
DOIs
StatePublished - Oct 1 2010

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    Tu, X., Das, K., Han, Q., Bauman, J. D., Clark, A. D., Hou, X., Frenkel, Y. V., Gaffney, B. L., Jones, R. A., Boyer, P. L., Hughes, S. H., Sarafianos, S. G., & Arnold, E. (2010). Structural basis of HIV-1 resistance to AZT by excision. Nature Structural and Molecular Biology, 17(10), 1202-1209. https://doi.org/10.1038/nsmb.1908