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Structural basis of HIV-1 resistance to AZT by excision

  1. Author:
    Tu, X. Y.
    Das, K.
    Han, Q. W.
    Bauman, J. D.
    Clark, A. D.
    Hou, X. R.
    Frenkel, Y. V.
    Gaffney, B. L.
    Jones, R. A.
    Boyer, P. L.
    Hughes, S. H.
    Sarafianos, S. G.
    Arnold, E.

  2. Author Address

    [Tu, Xiongying; Das, Kalyan; Bauman, Joseph D.; Clark, Arthur D., Jr.; Frenkel, Yulia V.; Sarafianos, Stefan G.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Tu, Xiongying; Das, Kalyan; Han, Qianwei; Bauman, Joseph D.; Clark, Arthur D., Jr.; Hou, Xiaorong; Frenkel, Yulia V.; Gaffney, Barbara L.; Jones, Roger A.; Sarafianos, Stefan G.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Biol, Piscataway, NJ 08854 USA. [Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA.;Arnold, E, Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA.;arnold@cabm.rutgers.edu
    1. Year: 2010
    2. Date: Oct
  2. Journal: Nature Structural & Molecular Biology
    1. 17
    2. 10
    3. Pages: 1202-+
  4. Type of Article: Article
  5. ISSN: 1545-9985
  1. 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.

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External Sources

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  2. DOI: 10.1038/nsmb.1908
  3. View record in Web of Science®
  4. WOS: 000282563600009

Library Notes

  1. Fiscal Year: FY2010-2011
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