Download MendeleyCrystal Structure of tert-Butyldimethylsilyl-spiroaminooxathioledioxide-thymine (TSAO-T) in Complex with HIV-1 Reverse Transcriptase (RT) Redefines the Elastic Limits of the Non-nucleoside Inhibitor-Binding Pocket.
Das, K., Bauman, J.D., Rim, A.S., Dharia, C., Clark, A.D., Camarasa, M.J., Balzarini, J., Arnold, E.(2011) J Med Chem 54: 2727-2737
- PubMed: 21446702
- DOI: https://doi.org/10.1021/jm101536x
- Primary Citation of Related Structures:
3QO9 - PubMed Abstract:
tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an embedded thymidine-analogue backbone; however, TSAO compounds invoke non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI-binding pocket, assuming a "dragon" shape, and interacts extensively with almost all the pocket residues. The structure also explains the structure-activity relationships and resistance data for TSAO compounds. The binding of 7 causes hyper-expansion of the pocket and significant rearrangement of RT subdomains. This nonoptimal complex formation is apparently responsible (1) for the lower stability of a RT (p66/p51) dimer and (2) for the lower potency of 7 despite of its extensive interactions with RT. However, the HIV-1 RT:7 structure reveals novel design features such as (1) interactions with the conserved Tyr183 from the YMDD-motif and (2) a possible way for an NNRTI to reach the polymerase active site that may be exploited in designing new NNRTIs.
Organizational Affiliation:
Center for Advanced Biotechnology and Medicine (CABM), Rutgers University, Piscataway, New Jersey 08854, United States. kalyan@cabm.rutgers.edu
