Toward High-throughput Crystal Structure Determination of PPAR Ligand-binding Domains in Complexes with Less Soluble Ligands

Abstract

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that are activated by endogenous fatty acids and synthetic compounds as ligands. We have been developing new phenylpropanoic acid derivatives based on structure-activity relationship studies that could reduce the side effects of existing clinical drugs. As a result, we have obtained many partial agonists that exhibit a moderate transcriptional activity while maintaining high specificity towards the receptors. However, because most of them are poorly soluble, protein-ligand interaction information has not yet been obtained by X-ray crystallography, which is essential for structure-activity relationship studies. In this paper, we report our ongoing crystallization experiments, which are aimed to develope a crystallization method for PPAR LBDs in solid-phase hydrogels that enables high-throughput protein-ligand complex crystal structure determination, using poorly soluble ligands.