Peroxisome proliferator activated receptor structure

Tugwood JD, Aldridge TC, Lambe KG, etal. 1996. Peroxisome proliferator-activated receptors Structures and function. Ann N Y Acad Sci 804 252-265. 

Zoete, V., Grosdidier, A., and Michielin, O. Peroxisome proliferator-activated receptor structures ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta 1771 (2007) 915-925. 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

The farnesoid X receptor is a member of the class of nuclear hormone receptors, which have key roles in development and homeostasis, as well as in many diseases like obesity, diabetes and cancer. The farnesoid X receptor shows structural similarity to the estrogen receptor (ER ), which mediates a broad spectrum of physiological functions such as regulation of reproduction, modulation of bone density, cholesterol transport and breast cancer. The farnesoid X receptor also shows similarity with the peroxisome proliferation-activated receptor y (PPARy), which is involved in fat metabolism, inflammatory and immune responses. The estrogen receptor (ER ), the peroxisome proliferation-activated receptor y (PPARy) and the farnesoid X receptor (FXR) can be clustered in a... 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Zhu, Y., Qi, C., Korenberg, J. R., Chen, X. N., Noya, D., Rao, M. S., and Reddy, J. K. (1995). Structural Organization of Mouse Peroxisome Proliferator-Activated Receptor Gamma (mPPARy) Gene Alternative Promoter Use and Different Splicing Yield Two mPPARy Isoforms. Proc. Natl. Acad. Sci. U.S.A. 92, 7921-7925. 

LPL M-CSFR MHC MHC-II MMCP MMP NG2 PDGF PPAR RANK Sca-1 SM22 L lipoprotein monocyte - colony stimulation factor receptor myosin heavy chain MHC class II mouse mast cell protease metalloproteinase proteoglycan heparan-sulfate related to pericytes activity platelet-derived growth factor peroxisome proliferator-activated receptor gamma receptor activator of NF-kappa 3 stem cell antigen 1 smooth cell protein structurally related to calponin, both actin and tropomyosin ligands... 

Xu, H.E. etal. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors, Proc. Natl Acad. Sci. USA, 24, 13919, 2001. 

The Glaxo group tvas the first to report the structure of a heterodimeric complex between two activated NHRs (peroxisome proliferator-activated receptor-y) PPAR-y and (retinoid X receptor-a) RXR-a. The structure (PDB entry 1FM6) of this heterodimer complex contains six components the two receptor LBDs, their two respective ligands, and two peptides derived from the steroid receptor co-activator-1 (SRC-1). These peptides contain a conserved LxxLL motif that is present in this class of co-activators. The complex is butterfly shaped, with both LBDs adopting the conserved helical sandwich fold previously reported for other ligand-bound nuclear receptors. PPAR-y contains 13 a-helices and four short / -strands, while RXR-a is composed of 11 a-helices and two short yS-strands [3]. This complex is illustrated in Fig. 1.1. 

A GRID/CPCA analysis of the three subtypes of Peroxisome Proliferator-Activated Receptors (PPARs) vas reported by Pirard [18] using three PPARa, eight PPARy, and three PPARd X-ray structures of the ligand binding domain (LED). 

Lewis DFV, Jacobs MN, Dickins M, Lake BG. Molecular modelling of the peroxisome proliferator-activated receptor a (PPARa) from human, rat and mouse, based on homology with the human PPARr crystal structure. Toxicology 2002 176 51-7. 

PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure. / Steroid Biochem Mol Biol 2003 84 117-32. 

Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptors superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid receptors. All members of this superfamily have a similar structure the amino-terminal region allows ligand-independent activation, confers con-... 

Li, Y, Kovach, A., Suino-Powell, K., Martynowski, D., and Xu, H. E. (2008). Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-lalpha. JBiol Chem 283, 19132-19139. 

Fig. 4.4 HRE structure of the RXR heterodimer. Shown isthe consensus sequence of the HREs of the RXR heterodimers (see Fig. 4.7) and the different possible arrangements of the hexameric half-site sequences. The hexamers can be arranged palindromically as inverted repeats (a), as everted repeats (b), or as direct repeats (c). n indicates the number of base pairs that lie between the two hexamers. RXR receptor for 9-cis-retinoic acid RAR receptor for all-trans retinoic acid T3R receptor for the T3 hormone PPAR peroxisome proliferator activated receptor VDR receptor for vitamin D3.

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