Structure-based analysis of the ultraspiracle protein and docking studies of putative ligands

Abstract

The ultraspiracle protein (USP) is the insect ortholog of the mammalian retinoid X receptor (RXR). Fundamental questions concern the functional role of USP as the heterodimerization partner of insect nuclear receptors such as the ecdysone receptor. The crystallographic structures of the ligand binding domain of USPs of Heliothis virescens and Drosophila melanogaster solved recently show that helix 12 is locked in an antagonist conformation raising the question whether USPs could adopt an agonist conformation as observed in RXRα. In order to investigate this hypothesis, a homology model for USP is proposed that allows a structural analysis of the agonist conformation of helix 12 based on the sequence comparison with RXR. For USP, one of the main issues concerns its function and in particular whether its activity is ligand independent or not. The x-ray structures strongly suggest that USP can bind ligands. Putative ligands have therefore been docked in the USP homology model. Juvenile hormones and juvenile hormone analogs were chosen as target ligands for the docking study. The interaction between the ligand and the receptor are examined in terms of the pocket shape as well as in terms of the chemical nature of the residues lining the ligand binding cavity.