4n8r
Crystal structure of RXRa LBD complexed with a synthetic modulator K-8008Crystal structure of RXRa LBD complexed with a synthetic modulator K-8008
Structural highlights
Publication Abstract from PubMedRetinoid X receptor-alpha (RXRalpha), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRalpha-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRalpha (tRXRalpha) with the p85alpha subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRalpha ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRalpha LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRalpha modulators and define a binding mechanism for regulating the nongenomic action of tRXRalpha. Sulindac-Derived RXRalpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.,Chen L, Wang ZG, Aleshin AE, Chen F, Chen J, Jiang F, Alitongbieke G, Zeng Z, Ma Y, Huang M, Zhou H, Cadwell G, Zheng JF, Huang PQ, Liddington RC, Zhang XK, Su Y Chem Biol. 2014 Apr 2. pii: S1074-5521(14)00077-5. doi:, 10.1016/j.chembiol.2014.02.017. PMID:24704507[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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