Coactivator Binding Promotes the Specific Interaction Between Ligand and the Pregnane X Receptor

Watkins, Ryan E.; Davis-Searles, Paula R.; Lambert, Mill H.; Redinbo, Matthew R.

doi:10.1016/s0022-2836(03)00795-2

Cited by 205 publications

(287 citation statements)

References 80 publications

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“…This indicates that, in the absence of ligand, ␣12 is conformationally flexible and can adopt both open and closed configurations. The predominance of the closed form seen in structural studies, in addition to data from thermal melt studies, suggests that the closed form of the apodomain may be energetically favored (33).…”

Section: Resultsmentioning

confidence: 92%

“…B, crystal structures of binary LBD complexes containing endogenous ligands, including the RXR ␣⅐9-cis retinoic acid complex (PDB 1FBY) (16), androgen receptor (AR)/dihydrotestosterone (DHT) complex (PDB 1I37) (35), and the ROR ␣/cholesterol complex (PDB 1N83) (34). C, crystal structures of ternary LBD/ligand/ coactivator complexes, including hRXR/ retinoic acid/SRC-1 (PDB 1FM6) (41), hPXR⅐SR12813⅐SRC-1 (PDB 1NRL) (33), and PPAR␣⅐GW409544⅐SRC-1 (PDB 1K7L) (40). The LBDs were aligned in roughly similar orientations.…”

Section: Resultsmentioning

confidence: 99%

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Structural Basis for HNF-4α Activation by Ligand and Coactivator Binding

Duda

In²,

Shoelson

2004

Journal of Biological Chemistry

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In addition to suggesting that fatty acids are endogenous ligands, our recent crystal structure of HNF-4␣ showed an unusual degree of structural flexibility in the AF-2 domain (helix ␣12). Although every molecule contained a fatty acid within its ligand binding domain, one molecule in each homodimer was in an open inactive conformation with ␣12 fully extended and colinear with ␣10. By contrast, the second molecule in each homodimer was in a closed conformation with ␣12 folded against the body of the domain in what is widely considered to be the active state. This indicates that although ligand binding is necessary, it is not sufficient to induce an activating structural transition in HNF-4␣ as is commonly suggested to occur for nuclear receptors. To further assess potential mechanisms of activation, we have solved a structure of human HNF-4␣ bound to both fatty acid ligand and a coactivator sequence derived from SRC-1. The mode of coactivator binding is similar to that observed for other nuclear receptors, and in this case, all of the molecules adopt the closed active conformation. We conclude that for HNF-4␣, coactivator rather than ligand binding locks the active conformation.As a member of the nuclear receptor family of transcription factors, HNF-4␣ can be separated into DNA and ligand binding domains (LBD).

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Structural Basis for HNF-4α Activation by Ligand and Coactivator Binding

Duda

In²,

Shoelson

2004

Journal of Biological Chemistry

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“…In a crystal structure of an agonist-bound NR that lacks the SRC-1 peptide, the corresponding lysine residue does not contact helix 12 at all (39). In addition, extension of helix 12 by three residues in mouse CAR did not influence the basal activity (61 (39,45). The above data indicate that LBD residues that interact with helix 12 also influence SRC-1 and/or NCoR binding.…”

Section: Modulation Of Human Car Activity-mentioning

confidence: 88%

“…2). PXR (45) and VDR (39) were used as template structures for human CAR and CAR/SRC-1 complex, whereas the structure of peroxisome proliferator-activated receptor ␣ complexed with silencing mediator of retinoid and thyroid receptors (46) was included to model the human CAR/NCoR complex. Non-conserved side chains were assigned by SCWRL 2.95 (47).…”

Section: Methodsmentioning

confidence: 99%

“…We noticed intriguing differences when comparing the CAR LBP to that of VDR and PXR, the templates for our homology models. The residue corresponding to the key residue Tyr 326 in CAR contacts the ligand in PXR (His 407 ) and in VDR (His 397 ) structures and their mutation appears to modulate ligand selectivity (45,67) that are crucial to CAR are not implicated in VDR or PXR ligand selectivity at all. This indicates that even though most of the LBP residues may correspond spatially, their functions differ tremendously.…”

Section: Modulation Of Human Car Activity-mentioning

confidence: 99%

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Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor

Jyrkkärinne

Windshügel

Mäkinen

et al. 2005

Journal of Biological Chemistry

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The human constitutive androstane receptor (CAR, NR1I3) is an important ligand-activated regulator of oxidative and conjugative enzymes and transport proteins. Because of the lack of a crystal structure of the ligand-binding domain (LBD), wide species differences in ligand specificity and the scarcity of well characterized ligands, the factors that determine CAR ligand specificity are not clear. To address this issue, we developed highly defined homology models of human CAR LBD to identify residues lining the ligand-binding pocket and to perform molecular dynamics simulations with known human CAR modulators. The roles of 22 LBD residues for basal activity, ligand selectivity, and interactions with co-regulators were studied using sitedirected mutagenesis, mammalian co-transfection, and yeast two-hybrid assays.

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Structure and Function of PXR and CAR

Zhou

2008

Nuclear Receptors in Drug Metabolism

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Coactivator Binding Promotes the Specific Interaction Between Ligand and the Pregnane X Receptor

Cited by 205 publications

References 80 publications

Structural Basis for HNF-4α Activation by Ligand and Coactivator Binding

Structural Basis for HNF-4α Activation by Ligand and Coactivator Binding

Amino Acids Important for Ligand Specificity of the Human Constitutive Androstane Receptor

Structure and Function of PXR and CAR

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