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Crystal structure of human T cell leukemia virus protease, a novel target for anticancer drug design

  1. Author:
    Li, M.
    Laco, G. S.
    Jaskolski, M.
    Rozycki, J.
    Alexandratos, J.
    Wlodawer, A.
    Gustchina, A.

  2. Author Address

    NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. Sci Applicat Int Corp, Basic Res program, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Polish Acad Sci, Inst Bioorgan Chem, Ctr Biocrystallog Res, PL-61704 Poznan, Poland. Adam Mickiewicz Univ Poznan, Dept Crystallog, Fac Chem, PL-61704 Poznan, Poland.;Gustchina, A, NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA.;alla@ncifcrf.gov
    1. Year: 2005
    2. Date: Dec
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 102
    2. 51
    3. Pages: 18332-18337
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    The successful development of a number of HIV-1 protease (PR) inhibitors for the treatment of AIDS has validated the utilization of retroviral PRs as drug targets and necessitated their detailed structural study. Here we report the structure of a complex of human T cell leukemia virus type 1 (HTLV-1) PR with a substrate-based inhibitor bound in subsites P5 through P5'. Although HTLV-1 PR exhibits an overall fold similar to other retroviral PRs, significant structural differences are present in several loop areas, which include the functionally important flaps, previously considered to be structurally highly conserved. Potential key residues responsible for the resistance of HTLV-1 PR to anti-HIV drugs are identified. We expect that the knowledge accumulated during the development of anti-HIV drugs, particularly in overcoming drug resistance, will help in designing a novel class of antileukemia drugs targeting HTLV-1 PR and in predicting their drug-resistance profile. The structure presented here can be used as a starting point for the development of such anticancer therapies.

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External Sources

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  2. DOI: 10.1073/pnas.0509335102
  3. View record in Web of Science®
  4. WOS: 000234174300018

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