Structural Insight into PPARγ Activation Through Covalent Modification with Endogenous Fatty Acids

Waku, Tsuyoshi; Shiraki, Takuma; Oyama, Takuji; Fujimoto, Yukari; Maebara, Kanako; Kamiya, Narutoshi; Jingami, Hisato; Morikawa, Kosuke

doi:10.1016/j.jmb.2008.10.039

Cited by 146 publications

(165 citation statements)

References 45 publications

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“…It has been previously reported that 15d-PGJ 2 reacts covalently with Cys-285 in vitro, inducing a particular nuclear receptor conformational change (33). More recently, the covalent modification of PPAR␥ Cys-285 was shown to lead to unique receptor conformational changes that resulted in differential regulation of downstream gene transcription (34). Of relevance, the interaction and alkylation of nucleophilic residues distal to the binding pocket may induce additional conformational changes that result in unique coregulator associations and interactions.…”

Section: Discussionmentioning

confidence: 99%

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

155

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The peroxisome proliferator-activated receptor-␥ (PPAR␥) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPAR␥ include lipids and antihyperglycemic drugs such as thiazolidinediones (TZDsThe rapidly expanding global burden of type II diabetes mellitus (DM) 3 and the concomitant increased risk for cardiovascular disease (1, 2) have motivated better understanding of relevant cell signaling pathways and potential therapeutic strategies. One major characteristic of metabolic syndrome and DM is insulin resistance, leading to hyperglycemia and dyslipidemia. Following initial clinical use of TZDs as anti-hyperglycemic agents to treat DM in the late 1990s, the nuclear receptor PPAR␥ was discovered as their molecular target. This receptor is expressed primarily in adipose tissue, muscle, and macrophages, where it regulates glucose uptake, lipid metabolism/ storage, and cell proliferation/differentiation (3-5). Thus, PPAR␥ ligands and allied downstream signaling events play a pivotal role in both the development and treatment of DM (6, 7). This is underscored by the observation that mutations in the C-terminal helix 12 of the ligand-binding domain (LBD) of PPAR␥ (e.g. P467L or V290M) are linked with severe insulin resistance and the onset of juvenile DM (8).The oxidizing inflammatory milieu contributing to the pathogenesis of obesity, diabetes, and cardiovascular disease also promotes diverse biomolecule oxidation, nitrosation, and nitration reactions by O 2 and ⅐ NO-derived species. Although oxidized fatty acids typically propagate proinflammatory conditions, the recently detected class of NO 2 -FA act as anti-inflammatory mediators. Nitroalkene derivatives of oleic acid (OA-NO 2 ) and linoleic acid (LNO 2 ) have been detected in healthy human blood and murine cardiac tissue. The levels of free/unesterified OA-NO 2 are ϳ1-3 nM in human plasma (9, 10), with OA-NO 2 produced at increased rates and present at higher concentrations during inflammatory and metabolic stress (11-13). The signaling actions of NO 2 -FA are primarily ascribed to the electrophilic olefinic carbon situated ␤ to the electron-withdrawing NO 2 substituent, facilitating kinetically rapid and reversible Michael addition with nucleophilic amino acids (i.e. Cys and His) (14). NO 2 -FA adduction of proteins and GSH occurs in model systems and clinically, with this reaction

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Section: Discussionmentioning

confidence: 99%

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Schöpfer

Cole

Groeger

et al. 2010

Journal of Biological Chemistry

155

View full text Add to dashboard Cite

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“…The diffraction data were collected at BL38B1 in SPring-8 (Harima, Japan), as described previously [16]. All data were processed using HKL2000 [18].…”

Section: Crystallization Data Collection and Model Refinementmentioning

confidence: 99%

“…Several polyunsaturated lipids, such as 15-deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ), activate the receptor-mediated transcription by covalently binding to a unique cysteine (Cys285) in the ligand-binding domain (LBD) [14,15]. Our recent study revealed the following facts [16]; (1) the covalent binding to endogenous fatty acids, such as 15d-PGJ 2, results in the structural alteration of the loop following helix H2 0 and in the rearrangement of the side-chain network around Cys285 within LBD; (2) the conformational difference of the loop provides the ligand-type specific effects in term of the distinct degree of the receptor activity; (3) Phe287, one of these repositioned residues, has an important role in receptor activation. However, it has been unclear how the conformational transmission by non-covalent binding to these ligands modulates receptor function before covalent bond formation, since the atomic details of the non-covalently bound state were unavailable.…”

Section: Introductionmentioning

confidence: 99%

Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ₂: Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands

et al. 2008

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Edited by Hans EklundKeywords: PPARc covalently bound ligand PPARc/RXRa activating process modulation mechanism Crystal structure a b s t r a c t 15-deoxy-D12,14 -prostaglandin J 2 (15d-PGJ 2 ) activates a nuclear receptor heterodimer, peroxisome proliferators-activated receptor c (PPARc)/ retinoid X receptor (RXRa) through covalent binding to Cys285 in PPARc ligand-binding domain (LBD). Here, we present the 1.9 Å crystal structure of C285S mutant LBD complexed with 15d-PGJ 2 , corresponding to the non-covalently bound state. The ligand lies adjacent to a hydrogen-bond network around the helix H2 and the nearby b-sheet. Comparisons with previous structures clarified the relationships between PPARc function and conformational alterations of LBD during the process of covalently binding ligands, such as 15d-PGJ 2 , and thus suggested a mechanism, by which these ligands modulate PPARc/RXRa function through conformational changes of the loop following helix H2 0 and the b-sheet.

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“…Unexpectedly, this series of high-resolution X-ray crystallographic structures uncover a conformational switch in the H2′-H3 loop of PPARδ's LBD upon ligand binding, a mechanism that may be shared across the superfamily of PPAR NRs. Studies of PPARγ have suggested that structural features of PPAR ligands may guide the conformations of H2′-H3 (46). As architectural changes and dynamics of H2′-H3 polypeptide segments induce significant differences in the surface features surrounding H2′-H3, it is likely that these ligand-mediated effects steer PPARδ interactions with coregulators.…”

Section: Resultsmentioning

confidence: 99%

Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

Baiga

Downes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ ligand-binding domain (LBD). A combination of atomic-resolution protein X-ray crystallographic structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineate structure-activity relationships (SARs) for PPARδ-selective targeting and structural modulation. We identify key ligand-induced conformational transitions of a conserved tryptophan side chain in the LBD that trigger reorganization of the H2′-H3 surface segment of PPARδ. The subtype-specific conservation of H2′-H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.nuclear receptors | drug discovery | structure-based design | peroxisome proliferator-activated receptor | cation-π interaction

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Structural Insight into PPARγ Activation Through Covalent Modification with Endogenous Fatty Acids

Cited by 146 publications

References 45 publications

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ₂: Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands

Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

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Structural Insight into PPARγ Activation Through Covalent Modification with Endogenous Fatty Acids

Cited by 146 publications

References 45 publications

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Covalent Peroxisome Proliferator-activated Receptor γ Adduction by Nitro-fatty Acids

Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ2: Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands

Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

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Atomic structure of mutant PPARγ LBD complexed with 15d‐PGJ₂: Novel modulation mechanism of PPARγ/RXRα function by covalently bound ligands