What is the origin of partial agonist activity of CBt-PMN for hRXR alpha?

Introduction Nuclear receptors are involved in the control of a variety of physiological processes. In particular, retinoid X receptor (RXR) agonists are well‐known to be effective in the treatment of various diseases but they sometimes cause side effect including elevation of blood triglyceride, weight gain, hepatomegaly and hypothyroidism. We have developed human RXRα partial agonist to reduce these side effects with keeping main effects. Recently we have reported CBt‐PMN (1) shows a potent glucose‐lowering effect without causing serious adverse effects. However, the origin of molecular basis of the partial agonistic activity for hRXRα is still controversial. In this research, we aimed to analyze crystal structure and molecular simulation results of the ligand binding domain of hRXRα in complex with CBt‐PMN, to elucidate molecular mechanism of partial agonist activity. Methods The cording sequence of hRXRα‐LBD (residues 227–462) was cloned to the vector pET15b, and Escherichia coli strain BL21(DE3) was used for protein expression. Complexes of CBt‐PMN and hRXRα‐LBD (residues 227–462) were crystalized and X‐ray diffraction data was collected. Fragment Molecular Orbital (FMO) method and Molecular Dynamics (MD) simulation were performed using the obtained crystal structure. Results & Discussion Crystal structure of hRXRα‐LBD/CBt‐PMN was determined at 2.4 Å and it showed a tetrameric hRXRα‐LBD oligomerization with CBt‐PMN bound to each hRXRα monomer. There were two types of CBt‐PMN binding conformation (form I and II ). By the FMO method, interaction between hRXRα/CBt‐PMN of form I is primarily contributed by the hydrophilic interactions through its carboxyl group, whereas that of form II is contributed by hydrophobic interactions. CBt‐PMN bound form shows more flexible nature at activation function‐2 (AF‐2) interface than that of bexarotene, full agonist for hRXRα by MD simulation. Support or Funding Information This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .