title: Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease.
abstract: Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus associated with several serious diseases, such as adult T-cell leukemia and tropical spastic paraparesis/myelopathy. For a number of years, the protease (PR) encoded by HTLV-1 has been a target for designing antiviral drugs, but that effort was hampered by limited available structural information. We report a high-resolution crystal structure of HTLV-1 PR complexed with a statine-containing inhibitor, a significant improvement over the previously available moderate-resolution structure. We also report crystal structures of the complexes of HTLV-1 PR with five different inhibitors that are more compact and more potent. A detailed study of structure-activity relationships was performed to interpret in detail the influence of the polar and hydrophobic interactions between the inhibitors and the protease.
authors.affiliation: Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Mi
authors.initials: M
authors.lastname: Li
authors.forename: Jeffrey-Tri
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.forename: Alla
authors.initials: A
authors.lastname: Gustchina
authors.forename: Alexander
authors.initials: A
authors.lastname: Wlodawer
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015368:Human T-lymphotropic virus 1 / Q000201:enzymology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C079711:HTLV-1 protease