Structure of Rev-erbα bound to N-CoR reveals a unique mechanism of nuclear receptor–co-repressor interaction

The ligand binding domain of nuclear receptor Rev-Erbα recruits corepressor NCoR to regulate target gene expression. Here the crystal structure of Rev-Erbα LBD in complex with a peptide from NCoR ID1 reveals formation of an anti-parallel β-sheet and also shows the corepressor a-helix in a registry different from those previously described in such complexes. Repression of gene transcription by the nuclear receptor Rev-erbα plays an integral role in the core molecular circadian clock. We report the crystal structure of a nuclear receptor–co-repressor (N-CoR) interaction domain 1 (ID1) peptide bound to truncated human Rev-erbα ligand-binding domain (LBD). The ID1 peptide forms an unprecedented antiparallel β-sheet with Rev-erbα, as well as an α-helix similar to that seen in nuclear receptor ID2 crystal structures but out of register by four residues. Comparison with the structure of Rev-erbβ bound to heme indicates that ID1 peptide and heme induce substantially different conformational changes in the LBD. Although heme is involved in Rev-erb repression, the structure suggests that Rev-erbα could also mediate repression via ID1 binding in the absence of heme. The previously uncharacterized secondary structure induced by ID1 peptide binding advances our understanding of nuclear receptor–co-repressor interactions.