2024-03-28T20:28:06Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1230092021-12-27T16:25:35Zcom_10261_81com_10261_5col_10261_334
DIGITAL.CSIC
author
Das, Krishna
author
Bauman, J. D.
author
Rim, A. S.
author
Dharia, C.
author
Clark, A. D.
author
Camarasa Rius, María José
author
Balzarini, Jan
author
Arnold, E.
funder
National Institutes of Health (US)
funder
Ministerio de Ciencia y Tecnología (España)
funder
Comunidad de Madrid
funder
University of Leuven
2011
Journal of Medicinal Chemistry 54: 2727-2737 (2011)
http://hdl.handle.net/10261/123009
10.1021/jm101536x
http://dx.doi.org/10.13039/100000002http://dx.doi.org/10.13039/501100006280http://dx.doi.org/10.13039/100012818
21446702
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.
eng
closedAccess
Crystal 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
artículo
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