Identification of ligand binding site on RXRγ using molecular docking and dynamics methods

Retinoid X receptors (RXR alpha, beta and gamma) are recently known to be cancer chemotherapies targets. The ligand binding domains of RXRs have been crystallized, but the information of RXR gamma ligand binding site is not yet available due to the lack of liganded complex. A thorough understanding of the ligand binding sites is essential to study RXRs and may result in cancer therapeutic breakthrough. Thus we aimed to study the RXR gamma ligand binding site and find out the differences between the three subtypes. Alignment and molecular simulation were carried out for identifying the RXR gamma ligand binding site, characterizing the RXR gamma ligand binding mode and comparing the three RXRs. The result has indicated that the RXR gamma ligand binding site is defined by helices H5, H10, beta-sheet s1 and the end loop. Besides hydrophobic interactions, the ligand 9-cis retinoic acid interacts with RXR gamma through a hydrogen bond with Ala106, a salt bridge with Arg95 and the pi-pi interactions with Phe217 and Phe218. The binding modes exhibit some similarities among RXRs, such as the interactions with Arg95 and Ala106. Nonetheless, owing to the absence of Ile47, Cys48, Ala50, Ala51 and residues 225 similar to 237 in the active site, the binding pocket in RXR gamma is two times larger than those of RXR alpha and RXR beta. Meanwhile, spatial effects of Trp84, Arg95, Ala106, Phe217 and Phe218 help to create a differently shaped binding pocket as compared to those of RXR alpha and RXR beta. Consequently, the ligand in RXR gamma undergoes a "standing" posing which is distinct from the other two RXRs.