A receptor-binding assay and X-ray crystal structure analysis demonstrated that the endocrine disruptor bisphenol A (BPA) strongly binds to human estrogen-related receptor gamma (ERR gamma). BPA is well anchored to the ligand-binding pocket, forming hydrogen bonds with its two phenol-hydroxyl groups. In this study, we found that 4-alpha-cumylphenol lacking one of its phenol-hydroxyl groups also binds to ERR gamma very strongly. The 2.0 angstrom crystal structure of the 4-alpha-cumylphenol/ERR gamma complex clearly revealed that ERR gamma's Leu345-beta-isopropyl plays a role in the tight binding of 4-alpha-cumylphenol and BPA, rotating in a back-and-forth induced-fit manner. 2008 Elsevier Inc. All rights reserved.