Asymmetry in the PPARγ/RXRα crystal structure reveals the molecular basis of heterodimerization among nuclear receptors

被引：517

作者：

Gampe, RT ^{[1
]}

Montana, VG ^{[1
]}

Lambert, MH ^{[1
]}

Miller, AB ^{[1
]}

Bledsoe, RK ^{[1
]}

Milburn, MV ^{[1
]}

Kliewer, SA ^{[1
]}

Willson, TM ^{[1
]}

Xu, HE ^{[1
]}

机构：

[1] Glaxo Wellcome Res & Dev, Res Triangle Pk, NC 27709 USA

来源：

MOLECULAR CELL | 2000年 / 5卷 / 03期

关键词：

D O I：

10.1016/S1097-2765(00)80448-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The nuclear receptor PPAR gamma/RXR alpha heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs G1262570 and the thiazolidinediones (TZDs). We report the crystal structures of the PPAR gamma and RXR alpha LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PPAR gamma agonist rosiglitazone or G1262570, and coactivator peptides. The PPAR gamma/RXR alpha heterodimer is asymmetric, with each LED deviated similar to 10 degrees from the C2 symmetry, allowing the PPAR gamma AF-2 helix to interact with helices 7 and 10 of RXR alpha. The heterodimer interface is composed of conserved motifs in PPAR gamma and RXR alpha that form a coiled coil along helix 10 with additional charge interactions from helices 7 and 9. The structures provide a molecular understanding of the ability of RXR to heterodimerize with many nuclear receptors and of the permissive activation of the PPAR gamma/RXR alpha heterodimer by 9cRA.

引用

页码：545 / 555

页数：11

共 39 条

[31] Nuclear-receptor ligands and ligand-binding domains [J].

Weatherman, RV ;

Fletterick, RJ ;

Scanlan, TS .

ANNUAL REVIEW OF BIOCHEMISTRY, 1999, 68 :559-581

[32] Atomic structure of progesterone complexed with its receptor [J].

Williams, SP ;

Sigler, PB .

NATURE, 1998, 393 (6683) :392-396

[33] Peroxisome proliferator-activated receptor agonists [J].

Willson, TM ;

Wahli, W .

CURRENT OPINION IN CHEMICAL BIOLOGY, 1997, 1 (02) :235-241

[34] The PPARs: From orphan receptors to drug discovery [J].

Willson, TM ;

Brown, PJ ;

Sternbach, DD ;

Henke, BR .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (04) :527-550

[35] A canonical structure for the ligand-binding domain of nuclear receptors [J].

Wurtz, JM ;

Bourguet, W ;

Renaud, JP ;

Vivat, V ;

Chambon, P ;

Moras, D ;

Gronemeyer, H .

NATURE STRUCTURAL BIOLOGY, 1996, 3 (01) :87-94

[36] Molecular recognition of fatty acids by peroxisome proliferator-activated receptors [J].

Xu, HE ;

Lambert, MH ;

Montana, VG ;

Parks, DJ ;

Blanchard, SG ;

Brown, PJ ;

Sternbach, DD ;

Lehmann, JM ;

Wisely, GB ;

Willson, TM ;

Kliewer, SA ;

Milburn, MV .

MOLECULAR CELL, 1999, 3 (03) :397-403

[37] Thyroid hormone receptor variant alpha 2 - Role of the ninth heptad in DNA binding, heterodimerization with retinoid X receptors, and dominant negative activity [J].

Yang, YZ ;

BurgosTrinidad, M ;

Wu, YF ;

Koenig, RJ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (45) :28235-28242

[38] DROSOPHILA ULTRASPIRACLE MODULATES ECDYSONE RECEPTOR FUNCTION VIA HETERODIMER FORMATION [J].

YAO, TP ;

SEGRAVES, WA ;

ORO, AE ;

MCKEOWN, M ;

EVANS, RM .

CELL, 1992, 71 (01) :63-72

[39] MUTATIONS THAT ALTER LIGAND-INDUCED SWITCHES AND DIMERIZATION ACTIVITIES IN THE RETINOID-X RECEPTOR [J].

ZHANG, XK ;

SALBERT, G ;

LEE, MO ;

PFAHL, M .

MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (06) :4311-4323

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