Crystal Structure of Human T Cell Leukemia Virus Protease, a Novel Target for Anticancer Drug Design

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-12, Vol.102 (51), p.18332-18337
• Main Authors: Li, Mi, Laco, Gary S., Jaskolski, Mariusz, Jan Rozycki, Alexandratos, Jerry, Wlodawer, Alexander, Alla Gustchina, Davies, David R.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Anti HIV agents; Anti-HIV Agents - chemistry; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Atoms; Biochemistry; Biological Sciences; Crystallography, X-Ray; Dimers; Drug Design; Enzymes; HIV 1; HIV 2; Human immunodeficiency virus; Human immunodeficiency virus 1; Human T lymphotropic virus 1; Human T-lymphotropic virus 1 - enzymology; Humans; Hydrogen bonds; Inhibitor drugs; Leukemia; Models, Molecular; Molecular Sequence Data; Molecules; Monomers; Protease inhibitors; Protease Inhibitors - chemistry; Proteases; Protein Structure, Tertiary; Sequence Alignment; Sequence Homology, Amino Acid; Structural Homology, Protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509335102

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 substratebased 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.