Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α

Abstract

The crystal structure of the human retinoid-X receptor RXR-alpha ligand-binding domain reveals a previously undiscovered fold of an antiparallel alpha-helical sandwich, packed as dimeric units. Two helices and one loop form the homodimerization surface, and hydrophobic heptad repeats participate in stabilizing the fold. The existence of a ligand-binding pocket is proposed that would allow 9-cis retinoic acid to interact with different functional modules, including the AF-2 activating domain. Several lines of evidence indicate that the overall structure is a prototype fold of ligand-binding domains of nuclear receptors.

Large-scale expression and purification of the human vitamin D receptor and its ligand-binding domain for structural studies

“…The N-terminal deletion of residues 1-135 breaks the predicted α-helix H1 of the LBD and this seems to affect the three-dimensional structure in such a way that ligand binding is abolished. The three-dimensional structures of apo-RXRα and holo-RARγ LBD show that H1 is an integral part of the LBD module, interacting with helices H3, H5 and H8 [15,16]. These structures and the results of protease sensitivity experiments on VDR [31] also indicate that binding of the ligand to the receptor causes conformational changes in the receptor molecules, which lead to a more compact structure than in the unbound state.…”

“…It mediates the binding of the ligand, the homodimerization and\or heterodimerization of the receptor and the transcriptional activation or repression of target genes. Crystal structures have been determined for the apo-RXRα [15], holo-RARγ [16] and holo-TRα [17] LBDs. However, no structure of any receptor LBD in both liganded and unliganded states has yet been solved.…”

“…The results also suggest that the binding of ligand brings about several conformational changes, which are absolute requirements for receptor activation. Binding of the ligand to the receptor might also cause the dissociation of repressor molecules, allowing association with general transcription factors, other DNA-binding proteins or co-activators [15][16][17][18][19].…”

Breast Cancer, Estrogen Receptor and Ligands

“…5C) and RAL [38]. ER LBDs are arranged in an antiparallel a-helical "sandwich" fold that was first described for the human RXRa apolipoprotein LBD [40]. The liganded ER LBD (Fig.…”

Characterization of the chimeric retinoic acid receptor RARα/VDR

“…18 In a now classical experiment, the glucocorticoid HRE became responsive to ␤-estradiol by replacing the C region of ER with that of GR. 19 Region E, the ligand-binding domain, is also involved in other structurally overlapping functions, [20][21][22][23][24] including transactivation 22 and dimerization. 23,24 The receptor polarity of DR HREs, with RXR at the 5′ HRE half-site, plus the freedom of rotation about the hinge region of the 3′-dimeric partner, 25 suggests the ligandbinding domains of RAR, VDR, and TR may be functionally interchangeable.…”