ERRγ-DBD undergoes dimerization and conformational rearrangement upon binding to the downstream site of the DR1 element.

The estrogen-related receptor (ERR) family members are reported to bind DNA elements as either monomer or dimer. However, to date, only one solution NMR structure of ERRβ in complex with a half-site DNA element has been reported. To better understand the DNA regulation mechanism, we determined the crystal structure of ERRγ-DBD bound to a natural DR1 element in Pla2g12b promoter to 2.2 Å resolution. Combined with biochemical assays, we show that ERRγ acts as a dimer and the C-terminal extension region undergoes conformational rearrangement when binding to the downstream DR1 element. In addition, the T-box region on the dimerization interface exhibits unique main-chain conformation. Thus, our structure presents a novel dimer interface for NR binding on DR1 DNA and provides a molecular basis for understanding the homodimer organization of ERR on DR1 elements.