Crystal Structure of the Human Liver X Receptor β Ligand-binding Domain in Complex with a Synthetic Agonist

Hoerer, S.; Schmid, Alex P.; Heckel, Armin; Budzinski, Ralph; Nar, Herbert

doi:10.1016/j.jmb.2003.10.033

Cited by 74 publications

(53 citation statements)

References 40 publications

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“…In the crystal structures of GW3965-bound LXR␤ and a binding coactivator peptide, the receptor adopts an agonistic conformation (22,46,47). Crystal structures of LXR␣ in the presence of GW3965 have not been reported, but our data clearly show that GW3965 will enhance the binding to both activators and repressors compared with the unliganded receptor.…”

Section: Discussionmentioning

confidence: 64%

A Novel Principle for Partial Agonism of Liver X Receptor Ligands

Albers

Blume

Schlueter

et al. 2006

Journal of Biological Chemistry

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Partial, selective activation of nuclear receptors is a central issue in molecular endocrinology but only partly understood. Using LXRs as an example, we show here that purely agonistic ligands can be clearly and quantitatively differentiated from partial agonists by the cofactor interactions they induce. Although a pure agonist induces a conformation that is incompatible with the binding of repressors, partial agonists such as GW3965 induce a state where the interaction not only with coactivators, but also corepressors is clearly enhanced over the unliganded state. The activities of the natural ligand 22(R)-hydroxycholesterol and of a novel quinazolinone ligand, LN6500 can be further differentiated from GW3965 and T0901317 by their weaker induction of coactivator binding. Using biochemical and cell-based assays, we show that the natural ligand of LXR is a comparably weak partial agonist. As predicted, we find that a change in the coactivator to corepressor ratio in the cell will affect NCoR recruiting compounds more dramatically than NCoRdissociating compounds. Our data show how competitive binding of coactivators and corepressors can explain the tissue-specific behavior of partial agonists and open up new routes to a rational design of partial agonists for LXRs.Nuclear receptors are a family of transcriptional regulators whose activity can be modulated by their binding to small molecule compounds, such as hormones and metabolites. For many members of the family, this property has allowed their use as drug targets (1). In most cases, however, full activation or inhibition of the receptor is not desired. Instead, agonists are required that only partially activate the receptor. Partial agonists can display tissue-specific activation or repression of nuclear receptors, as has been shown for the estrogen receptor partial agonist raloxifen (2). However, little is known about the molecular mechanisms leading to partial versus full agonism.Another example for nuclear receptors, which, if they are to be used as drug targets, require partial agonists, are the liver X receptors ␣ (LXR␣, 2 NR1H3) and ␤ (LXR␤, NR1H2). They have been shown to play a central role in the transcriptional regulation of lipid and cholesterol homeostasis and inflammation (3-7). Activation of LXR-dependent transcription leads to increased expression of cholesterol transporters (8 -11) and has been shown to enhance the efflux of cholesterol from macrophages (10 -12), reducing the formation of atherosclerotic plaques (13)(14)(15). This observation has raised hopes that the manipulation of LXR activity would be of therapeutic value in the treatment of lipid disorders and atherosclerosis. However, activation of LXRs by agonistic compounds induces the expression of enzymes involved in the synthesis of fatty acids in liver cells (16 -19). As a consequence, agonists for LXRs cause liver steatosis and elevated serum triglyceride levels in mice (19,20). Thus, to develop LXR ligands as drugs for the treatment of atherosclerosis, partial, selective activator...

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Section: Discussionmentioning

confidence: 64%

A Novel Principle for Partial Agonism of Liver X Receptor Ligands

Albers

Blume

Schlueter

et al. 2006

Journal of Biological Chemistry

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“…In the complex of LXR␤-LBD with GW3965 (45), this cavity is occupied by isopropanol, whereas in the complex of LXR␤-LBD with 24(S),25-epoxycholesterol (46) the cavity is occupied by water molecules. Single water molecules also occupy volume in this region in the structures of LXR␤-LBD in complex with ligands T-0901317 (47) and A1462 (47). In the structure of FXR-LBD complexed with 6-ethyl-chenodeoxycholic acid (48) and in the structures of LXR␤-LBD in complex with 24(S),25-epoxycholesterol (46) the volume corresponding to this cavity extends to the surface of the molecule at a location surrounded by residues from the helix H1/H2 region, the C terminus of helix H5, strand s1, and the N terminus of helix H8.…”

Section: Discussionmentioning

confidence: 99%

The X-ray Structure of a Hemipteran Ecdysone Receptor Ligand-binding Domain

Carmichael

Lawrence

Graham³

et al. 2005

Journal of Biological Chemistry

106

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The ecdysone receptor is a hormone-dependent transcription factor that plays a central role in regulating the expression of vast networks of genes during development and reproduction in the phylum Arthropoda. The functional receptor is a heterodimer of the two nuclear receptor proteins ecdysone receptor (EcR) and ultraspiracle protein. The receptor is the target of the environmentally friendly bisacylhydrazine insecticides, which are effective against Lepidoptera but not against Hemiptera or several other insect orders. Here we present evidence indicating that much of the selectivity of the bisacylhydrazine insecticides can be studied at the level of their binding to purified ecdysone receptor ligand-binding domain (LBD) heterodimers. We report the crystal structure of the ecdysone receptor LBD heterodimer of the hemipteran Bemisia tabaci (Bt, sweet potato whitefly) in complex with the ecdysone analogue ponasterone A. Although comparison with the corresponding known LBD structure from the lepidopteran Heliothis virescens (Hv) ecdysone receptor revealed the overall mode of ponasterone A binding to be very similar in the two cases, we observed that the BtEcR ecdysteroid-binding pocket is structured differently to that of HvEcR in those parts that are not in contact with ponasterone A. We suggest that these differences in the ligand-binding pocket may provide a molecular basis for the taxonomic order selectivity of bisacylhydrazine insecticides. The nuclear receptor (NR)1 family of proteins plays a crucial role in the regulation of transcription, and its members include the receptors for steroid hormones, vitamins, thyroid hormones, and bile acids (1). The human genome contains about 48 members of this family, and these have been studied extensively as therapeutic targets (2). The Arthropoda display a more limited suite of NRs (3) about 21 of which occur in Drosophila melanogaster. Among these is the receptor for the major arthropod steroid hormone, 20-hydroxyecdysone, which is involved in the regulation of insect molting, metamorphosis, and reproduction (4 -9). The receptor is absent from mammals and is thus potentially useful as a safe insecticide target. Indeed members of the bisacylhydrazine family exert their insecticidal activity by binding to the ecdysone receptor and exhibit remarkable taxonomic order selectivity (10, 11). These compounds act selectively on the Lepidoptera and certain Coleoptera (10) but are ineffective against insects of the hemipteran order and therefore cannot be used to control certain insect pests. A study (12) of two hemipteran insect predators (Geocoris punctipes and Orius insidiosus) showed that these beneficial (predatory) hemipterans are relatively insensitive to the bisacylhydrazine tebufenozide, whereas lepidopteran insect pests are susceptible. An improved understanding of variation in the structure of the ligand-binding pockets of ecdysone receptors and the basis of the specificity of these compounds at the atomic level of detail of their interaction with the receptor may aid ...

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“…Structures have been solved for LXR␤ bound to the natural agonist 24(S),25-epoxycholesterol (eCH) and the synthetic agonist T0901317 (Hoerer et al, 2003;Williams et al, 2003). The ligands are retained in the pocket primarily through hydrophobic interactions that orient the A ring of eCH toward helix 1 and the D ring and epoxide tail toward the C-terminal end of helix 10.…”

Section: Lxr␣ and ␤mentioning

confidence: 99%

International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor

Moore¹,

Kato²,

Xie³

et al. 2006

Pharmacol Rev

187

154

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Abstract--The nuclear receptors of the NR1H and NR1I subgroups include the constitutive androstane receptor, pregnane X receptor, farnesoid X receptors, liver X receptors, and vitamin D receptor. The newly emerging functions of these related receptors are under the control of metabolic pathways, including metabolism of xenobiotics, bile acids, cholesterol, and calcium. This review summarizes results of structural, pharmacologic, and genetic studies of these receptors.

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Crystal Structure of the Human Liver X Receptor β Ligand-binding Domain in Complex with a Synthetic Agonist

Cited by 74 publications

References 40 publications

A Novel Principle for Partial Agonism of Liver X Receptor Ligands

A Novel Principle for Partial Agonism of Liver X Receptor Ligands

The X-ray Structure of a Hemipteran Ecdysone Receptor Ligand-binding Domain

International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor

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