科研之友
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摘要
Retinoic acid is an important regulator of cell differentiation which plays major roles in embryonic development and tissue remodeling. The biological action of retinoic acid is mediated by three nuclear receptors denoted RAR alpha, beta and gamma. Multiple studies support that RAR beta possesses functional characteristics of a tumor suppressor and indeed, its expression is frequently lost in neoplastic tissues. However, it has been recently reported that RAR beta could also play a role in mammary gland tumorigenesis, thus demonstrating the important but yet incompletely understood function of this receptor in cancer development. As a consequence, there is a great need for RAR beta-selective agonists and antagonists as tools to facilitate the pharmacological analysis of this protein in vitro and in vivo as well as for potential therapeutic interventions. Here we provide experimental evidences that the novel synthetic retinoid BMS948 is an RAR beta-selective ligand exhibiting a full transcriptional agonistic activity and activating RAR beta as efficiently as the reference agonist TTNPB. In addition, we solved the crystal structures of the RAR beta ligand-binding domain in complex with BMS948 and two related compounds, BMS641 and BMS411. These structures provided a rationale to explain how a single retinoid can be at the same time an RAR alpha antagonist and an RAR beta full agonist, and revealed the structural basis of partial agonism. Finally, in addition to revealing that a flip by 180 degrees of the amide linker, that usually confers RAR alpha selectivity, accounts for the RAR beta selectivity of BMS948, the structural analysis uncovers guidelines for the rational design of RAR beta-selective antagonists.
- 出版日期2015-5-1
- 单位中国科学院
