Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

Xu, H. Eric; Lambert, Millard H.; Montana, V.G.; Plunket, Kelli D.; Moore, Linda B.; Collins, Jon L.; Oplinger, Jeffrey A.; Kliewer, Steven A.; Gampe, Robert T.; McKee, David D.; Moore, John T.; Willson, Timothy M.

doi:10.1073/pnas.241410198

Cited by 510 publications

(484 citation statements)

References 32 publications

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“…2C), suggesting that NR LBD dimers contact both TRAP220 motifs. This is consistent with the crystal structures of agonist-bound LBD homodimers or RXR␣ LBD heterodimers in combination with short LXXLL peptides, or a partial SRC1 NID, which show that both LBDs in the NR dimer are occupied with a LXXLL core ␣-helix (12,13,34,53). An exception in our experiments was the RXR␣ LBD, which required only a functional LXM1 for strong binding (Fig.…”

Section: Trap220 Nuclear Receptor Binding Specificitysupporting

confidence: 88%

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

Coulthard¹,

Matsuda

Heery

2003

Journal of Biological Chemistry

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The interaction of coactivators with the ligand-binding domain of nuclear receptors (NRs) is mediated by amphipathic ␣-helices containing the signature motif LXXLL. TRAP220 contains two LXXLL motifs (LXM1 and LXM2) that are required for its interaction with NRs. Here we show that the nuclear receptor interaction domain (NID) of TRAP220 interacts weakly with Class I NRs. In contrast, SRC1 NID binds strongly to both Class I and Class II NRs. Interaction assays using nine amino acid LXXLL core motifs derived from SRC1 and TRAP220 revealed no discriminatory NR binding preferences. However, an extended LXM1 sequence containing amino acids ؊4 to ؉9, (where the first conserved leucine is ؉1) showed selective binding to thyroid hormone receptor and reduced binding to estrogen receptor. Replacement of either TRAP220 LXXLL motif with the corresponding 13 amino acids of SRC1 LXM2 strongly enhanced the interaction of the TRAP220 NID with the estrogen receptor. Mutational analysis revealed combinatorial effects of the LXM1 core and flanking sequences in the determination of the NR binding specificity of the TRAP220 NID. In contrast, a mutation that increased the spacing between TRAP220 LXM1 and LXM2 had little effect on the binding properties of this domain. Thus, a 13-amino acid sequence comprising an extended LXXLL motif acts as the key determinant of the NR binding specificity of TRAP220. Finally, we show that the NR binding specificity of full-length TRAP220 can be altered by swapping extended LXM sequences.

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Section: Trap220 Nuclear Receptor Binding Specificitysupporting

confidence: 88%

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

Coulthard¹,

Matsuda

Heery

2003

Journal of Biological Chemistry

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“…The GW0072 compound is a poor transactivator and can antagonize TZD-driven adipocyte differentiation (24). Taken together, these observations suggest that the specific hydrogen bonding interactions seen between the agonists and AF2 could act as a necessary molecular switch for transactivation to occur (22,24).…”

mentioning

confidence: 87%

“…Crystal structures of PPAR␣, -␦, and -␥ ligand-binding domains (LBDs), in complex with various agonists (5,(21)(22)(23), reveal a common binding mode where the ligands form specific hydrogen bonds with residues in, and in the vicinity of, helix 12, also known as activation function 2 (AF2). It is generally believed that agonist binding to NRs induces changes in the dynamics and position of helix 12, which in turn facilitates the recruitment of coactivator proteins resulting in an activation of the transcriptional machinery.…”

mentioning

confidence: 99%

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Östberg

Svensson²,

Selén³

et al. 2004

Journal of Biological Chemistry

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The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPAR␣/␥ modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.

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“…The observation that binding of non-fluorescent ligands significantly quenched the emission of PPARαΔAB aromatic amino acid residues (Figs. [1][2][3][4] suggests that ligand binding altered the conformation of PPARα. To further examine whether the binding of naturally-occurring VLCFA alter PPARα structure, the effect of these ligands on the circular dichroic (CD) spectra of PPARα was examined.…”

Section: Effect Of Very-long-chain Fatty Acids On Pparα Secondary Strmentioning

confidence: 99%

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

2006

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Very long chain fatty acids (VLCFA) and branched-chain fatty acids (BCFA) are potent inducers of the peroxisome proliferator-activated receptor PPARα, a nuclear receptor that enhances transcription of peroxisomal enzymes mediating β-oxidation of these potentially toxic fatty acids. However, it is not known whether the respective free fatty acids or their activated metabolites, i.e. CoA thioesters: (i) are the endogenous high-affinity PPARα ligands, (ii) alter PPARα conformation, and (iii) alter recruitment of coregulatory proteins to PPARα. As shown by quenching of PPARα intrinsic amino acid fluorescence, PPARα exhibited high affinity (3-29nM K d s) for the CoA thioesters of the common (C20-C24) VLCFA. In contrast, with the exception of arachidonic acid (K d =20nM), PPARα only weakly bound the VLCFA. PPARα also exhibited higher affinity for the CoA thioesters of BCFA (phytanoyl-CoA, pristanoyl-CoA; K d s near 11nM) than for the respective free branched-chain fatty acids. As shown by circular dichroism, the high affinity VLCFA-CoA and BCFA-CoA strongly altered PPARα conformation. Likewise, the high affinity VLCFA-CoA and BCFA-CoA altered cofactor recruitment to PPARα as shown by co-immunoprecipitation from liver homogenates. In contrast, nearly all the respective free fatty acids elicited only weak conformational changes in PPARα and did not alter co-factor recruitment to PPARα. In summary, the CoA thioesters of verylong-chain and branched-chain fatty acids are much more potent PPARα ligands than the free acids, resulting in altered PPARα conformation and cofactor recruitment. Since these are hallmarks of ligands-activated nuclear receptors, this suggests that the CoA thioesters are the active forms of these PPARα ligands.

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Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

Cited by 510 publications

References 32 publications

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

An Extended LXXLL Motif Sequence Determines the Nuclear Receptor Binding Specificity of TRAP220

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

Very-Long-Chain and Branched-Chain Fatty Acyl-CoAs Are High Affinity Ligands for the Peroxisome Proliferator-Activated Receptor α (PPARα)

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