Crystal structures of inhibitor complexes of human T-cell leukemia virus (HTLV-1) protease.
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.
Satoh
Tadashi
T
Protein Structure Section, Macromolecular Crystallography Laboratory, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
Li
Mi
M
Nguyen
Jeffrey-Tri
JT
Kiso
Yoshiaki
Y
Gustchina
Alla
A
Wlodawer
Alexander
A
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
D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C079711:HTLV-1 protease