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dc.contributor.authorDas, Krishna-
dc.contributor.authorBauman, J. D.-
dc.contributor.authorRim, A. S.-
dc.contributor.authorDharia, C.-
dc.contributor.authorClark, A. D.-
dc.contributor.authorCamarasa Rius, María José-
dc.contributor.authorBalzarini, Jan-
dc.contributor.authorArnold, E.-
dc.identifierdoi: 10.1021/jm101536x-
dc.identifierissn: 0022-2623-
dc.identifiere-issn: 1520-4804-
dc.identifier.citationJournal of Medicinal Chemistry 54: 2727-2737 (2011)-
dc.description.abstracttert-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.-
dc.description.sponsorshipWe acknowledge Ann Stock, Matthew Miller, and the X-ray data collection facility at CABM for help with diffraction data collection. We are grateful to the U.S. National Institutes of Health (NIH; grants R37 MERIT Award AI 27690 to E.A.; R21 Award AI 087201 to K.D.), the KU Leuven (GOA 10/014 to J. B.), the Spanish MICINN(project SAF2009-13914-C02 to M.-J. C.), and the Comunidad de Madrid (project BIPEDD-CM ref S-BIO-0214-2006 to M.-J.C.) for financial support.-
dc.publisherAmerican Chemical Society-
dc.titleCrystal 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-
dc.description.versionPeer Reviewed-
dc.contributor.funderNational Institutes of Health (US)-
dc.contributor.funderMinisterio de Ciencia y Tecnología (España)-
dc.contributor.funderComunidad de Madrid-
dc.contributor.funderUniversity of Leuven-
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