DBD: The greater than 60% identity between the DNA binding domains (DBDs) of ERRgamma and ERalpha (see figure) results in ERRgamma being able to bind the estrogen response element (ERE: AGGTCA...TGACCT). However, ERRgamma also binds to what was originally identified as the consensus sequence for steroidogenic factor 1 (SF1, SFRE: TCAAGGTCA) (Horard and Vanacker, 2003).

LBD: A key difference between ERRgamma and most members of the nuclear receptor superfamily is the regulation of its transcriptional activity. There is only about 23% sequence identity between classical ERalpha and ERRgamma in the ligand binding domain (LBD) (see figure). Therefore, while ERalpha (like most nuclear receptors) is dependent upon ligand for full activation, ERRgamma and the other members of the ERR family exhibit constitutive transcriptional activity. None of the ERR family members are affected by estradiol (E2) stimulation because their LBDs cannot accommodate E2 binding (discussed in Ariazi and Jordan, 2006). However, ERRgamma transcriptional activity at EREs and SFREs can be inhibited by 4-hydroxytamoxifen (4HT) and the synthetic estrogen diethylstilbestrol (Greschik et al., 2002; Greschik et al., 2004; Yu and Forman, 2005). In contrast, 4HT-bound ERRgamma acquires the ability to positively regulate transcription at activator protein-1 (AP1) sites (Huppunen et al., 2004), but the mechanism by which this occurs is not clear. ERRgamma constitutive activity can be enhanced or stabilized by the synthetic agonist GSK4716 (Yu and Forman, 2005; Zuercher et al., 2005), the endocrine disruptor Bisphenol A (BPA) (Matsushima et al., 2007; Takayanagi et al., 2006), and a variant of this compound (4-alpha-cumylphenol) (Matsushima et al., 2008). ERRgamma constitutive activity has also recently been shown to be inhibited by kaempferol, a dietary flavonoid (Wang et al., 2009).

Coactivators/Corepressors: Like other nuclear receptors, ERRgamma transcriptional activity is modulated by binding to other proteins that can serve as coactivators or corepressors. Coactivators and corepressors bind directly to nuclear receptors, most often within the carboxyl-terminal activation function-2 (AF2) domain that participates in ligand-binding but some can exert their effects by binding to the amino-terminal AF1 domain or the flexible hinge region of the receptor (Hall and McDonnell, 2005). Among the coactivators that have been demonstrated to bind and activate ERRgamma are PPARGC1A (also known as PGC-1alpha), TLE1, NCOA1, NCOA2 and, under certain circumstances, NRIP1 (Gowda et al., 2006; Sanyal et al., 2004). PPARGC1A is best known as a coactivator for peroxisome proliferator-activated receptor gamma, but it is also able to enhance ERRgamma activity in an AF1-dependent manner (Hentschke et al., 2002). TLE1 can also enhance ERRgamma activity by binding to its AF1 domain, and the coactivator function of TLE1 in this context is unique because this protein typically functions as a repressor for Drosophila and mammalian high mobility group (HMG) box transcription factors. TLE1 also has no known interactions with classical ERalpha or any other nuclear receptor (Hentschke and Borgmeyer, 2003). In contrast, NCOA1 and NCOA2 are well-known AF2-dependent coactivators of ERalpha and other nuclear receptors, including ERRgamma (reviewed in Hall and McDonnell, 2005).