Structural insight into the constitutive repression function of the nuclear receptor Rev-erbβ

The Rev-erb family is an orphan nuclear receptor acting as a negative regulator of transcription. Rev-erb alpha and Rev-eft are crucial components of the circadian clock and involved in various lipid homeostasis. They are unique nuclear receptors that lack the activation function 2 helix (AF2-helix) required for ligand-dependent activation by other members of nuclear receptors. Here, we report the crystal structure of Rev-erb beta (NR1D2) in a dimeric arrangement. The putative ligand-binding pocket (LBP) of Rev-erb beta is filled with bulky hydrophobic residues resulting in a residual cavity size that is too small to allow binding of any known ligand molecules. However, an alternative conformation of the putative LBP observed in another crystal form suggests the flexibility of this region. The kinked conformation of helix H11 allows helix H11 to bend toward helix H3 over the putative ligand binding pocket by filling and closing the cavity with its side-chains. In the absence of the AF2-helix and a cognate ligand, Rev-eft appears to stabilize the hydrophobic cluster in the putative ligand binding pocket and provide a structural platform for co-repressor binding by adopting the unique geometry of helix H11, a suitable conformation for the constitutive repression activity. (c) 2007 Elsevier Ltd. All rights reserved.