PDBsum entry 3prg

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protein links
Nuclear receptor PDB id
Protein chain
267 a.a. *
* Residue conservation analysis
PDB id:
Name: Nuclear receptor
Title: Ligand binding domain of human peroxisome proliferator activated receptor
Structure: Peroxisome proliferator activated receptor gamma. Chain: a. Fragment: ligand binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Cellular_location: nucleus. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.90Å     R-factor:   0.209     R-free:   0.271
Authors: J.Uppenberg,C.Svensson,M.Jaki,G.Bertilsson,L.Jendeberg, A.Berkenstam
Key ref:
J.Uppenberg et al. (1998). Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J Biol Chem, 273, 31108-31112. PubMed id: 9813012 DOI: 10.1074/jbc.273.47.31108
24-Aug-98     Release date:   30-Aug-99    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
505 a.a.
267 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     4 terms  


DOI no: 10.1074/jbc.273.47.31108 J Biol Chem 273:31108-31112 (1998)
PubMed id: 9813012  
Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma.
J.Uppenberg, C.Svensson, M.Jaki, G.Bertilsson, L.Jendeberg, A.Berkenstam.
The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear receptor supergene family and are considered as key sensors of both lipid and glucose homeostasis. The role of the PPARgamma isoform in glucose metabolism is illustrated by the fact that anti-diabetic thiazolidinediones have been shown to be bona fide PPARgamma ligands. Here we report the crystal structure of apo-PPARgamma ligand binding domain (LBD) determined to 2.9-A resolution. Although the structure of apo-PPARgamma-LBD retains the overall fold described previously for other nuclear receptor LBDs, three distinct structural differences are evident. 1) The core AF-2 activation domain of apo-PPARgamma LBD is folded back toward the predicted ligand binding pocket similar to that observed in the holo-forms of other nuclear receptors. 2) The proposed ligand binding pocket of apo-PPARgamma-LBD is larger and more accessible to the surface in contrast to other LBDs. 3) The region of the LBD called the omega-loop is extended in PPARgamma and contains additional structural elements. Taken together, the apo-PPARgamma-LBD structure is in several aspects different from previously described LBDs. Given the central role of PPARgamma as a mediator in glucose regulation, the structure should be an important tool in the development of improved anti-diabetic agents.
  Selected figure(s)  
Figure 1.
Fig. 1. A stereo image of apo-PPAR -LBD. The protein adopts a conformation for helix 12 similar to RAR and PR, both of which have ligands bound. The figure was made with Molscript (33).
Figure 3.
Fig. 3. A comparison of the ligand binding pockets of holo-RAR (a), holo-PR (b), and apo-PPAR (c). A cavity search was performed with the program Voidoo (34). The surfaces displayed represent accessible surfaces of cavities using a 1.8-Å probe. In PR and RAR , the cavities are closed, whereas for PPAR it is accessible from the outside of the protein (Protein Data Bank entries: 2LBD for RAR and 1A28 for PR). The figure was made with O (28).
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (1998, 273, 31108-31112) copyright 1998.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20496064 J.Fidelak, S.Ferrer, M.Oberlin, D.Moras, A.Dejaegere, and R.H.Stote (2010).
Dynamic correlation networks in human peroxisome proliferator-activated receptor-γ nuclear receptor protein.
  Eur Biophys J, 39, 1503-1512.  
20372994 S.Mukherjee, and S.Mani (2010).
Orphan nuclear receptors as targets for drug development.
  Pharm Res, 27, 1439-1468.  
19746174 S.N.Lewis, J.Bassaganya-Riera, and D.R.Bevan (2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
  PPAR Res, 2010, 861238.  
20530906 W.Li, Y.Yuan, Z.Luo, X.Zheng, L.Zhao, W.Duan, and Y.Yu (2010).
Bacterial expression, refolding, functional characterization, and mass spectrometric identification of full-length human PPAR-gamma.
  Biosci Biotechnol Biochem, 74, 1173-1180.  
19721807 G.N.Brooke, and C.L.Bevan (2009).
The role of androgen receptor mutations in prostate cancer progression.
  Curr Genomics, 10, 18-25.  
18501204 A.L.Parrill (2008).
Lysophospholipid interactions with protein targets.
  Biochim Biophys Acta, 1781, 540-546.  
18665581 A.S.Felts, B.S.Siegel, S.M.Young, C.W.Moth, T.P.Lybrand, A.J.Dannenberg, L.J.Marnett, and K.Subbaramaiah (2008).
Sulindac derivatives that activate the peroxisome proliferator-activated receptor gamma but lack cyclooxygenase inhibition.
  J Med Chem, 51, 4911-4919.  
17929009 D.Genest, N.Garnier, A.Arrault, C.Marot, L.Morin-Allory, and M.Genest (2008).
Ligand-escape pathways from the ligand-binding domain of PPARgamma receptor as probed by molecular dynamics simulations.
  Eur Biophys J, 37, 369-379.  
18779870 I.Sainis, K.Vareli, V.Karavasilis, and E.Briasoulis (2008).
PPARgamma: The Portrait of a Target Ally to Cancer Chemopreventive Agents.
  PPAR Res, 2008, 436489.  
18670616 J.J.Bright, S.Kanakasabai, W.Chearwae, and S.Chakraborty (2008).
PPAR Regulation of Inflammatory Signaling in CNS Diseases.
  PPAR Res, 2008, 658520.  
18554251 O.A.Gani, and I.Sylte (2008).
Ligand-induced stabilization and activation of peroxisome proliferator-activated receptor gamma.
  Chem Biol Drug Des, 72, 50-57.  
17906643 Lera, W.Bourguet, L.Altucci, and H.Gronemeyer (2007).
Design of selective nuclear receptor modulators: RAR and RXR as a case study.
  Nat Rev Drug Discov, 6, 811-820.  
17357171 G.Fracchiolla, A.Laghezza, L.Piemontese, G.Carbonara, A.Lavecchia, P.Tortorella, M.Crestani, E.Novellino, and F.Loiodice (2007).
Synthesis, Biological Evaluation, and Molecular Modeling Investigation of Chiral Phenoxyacetic Acid Analogues with PPARalpha and PPARgamma Agonist Activity.
  ChemMedChem, 2, 641-654.  
17937915 J.B.Bruning, M.J.Chalmers, S.Prasad, S.A.Busby, T.M.Kamenecka, Y.He, K.W.Nettles, and P.R.Griffin (2007).
Partial agonists activate PPARgamma using a helix 12 independent mechanism.
  Structure, 15, 1258-1271.
PDB codes: 2q59 2q5p 2q5s 2q61 2q6r 2q6s
17259669 E.S.Tien, D.B.Hannon, J.T.Thompson, and J.P.Vanden Heuvel (2006).
Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha).
  PPAR Res, 2006, 69612.  
16317783 F.Ye, Z.S.Zhang, H.B.Luo, J.H.Shen, K.X.Chen, X.Shen, and H.L.Jiang (2006).
The dipeptide H-Trp-Glu-OH shows highly antagonistic activity against PPARgamma: bioassay with molecular modeling simulation.
  Chembiochem, 7, 74-82.  
16305809 L.Guo, and R.Tabrizchi (2006).
Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance.
  Pharmacol Ther, 111, 145-173.  
15819976 A.Möglich, D.Weinfurtner, T.Maurer, W.Gronwald, and H.R.Kalbitzer (2005).
A restraint molecular dynamics and simulated annealing approach for protein homology modeling utilizing mean angles.
  BMC Bioinformatics, 6, 91.  
15671120 A.Möglich, D.Weinfurtner, W.Gronwald, T.Maurer, and H.R.Kalbitzer (2005).
PERMOL: restraint-based protein homology modeling using DYANA or CNS.
  Bioinformatics, 21, 2110-2111.  
15722453 L.Yue, F.Ye, C.Gui, H.Luo, J.Cai, J.Shen, K.Chen, X.Shen, and H.Jiang (2005).
Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.
  Protein Sci, 14, 812-822.  
14717706 C.Yu, L.Chen, H.Luo, J.Chen, F.Cheng, C.Gui, R.Zhang, J.Shen, K.Chen, H.Jiang, and X.Shen (2004).
Binding analyses between Human PPARgamma-LBD and ligands.
  Eur J Biochem, 271, 386-397.  
11963993 A.Ohno, M.Shimizu, and S.Yamada (2002).
Fluorinated vitamin D analogs to probe the conformation of vitamin D in its receptor complex: 19F-NMR studies and biological activity.
  Chem Pharm Bull (Tokyo), 50, 475-483.  
12101224 I.Dussault, M.Lin, K.Hollister, M.Fan, J.Termini, M.A.Sherman, and B.M.Forman (2002).
A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity.
  Mol Cell Biol, 22, 5270-5280.  
12115546 K.Steketee, L.Timmerman, A.C.Ziel-van der Made, P.Doesburg, A.O.Brinkmann, and J.Trapman (2002).
Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer.
  Int J Cancer, 100, 309-317.  
11772424 O.Ziouzenkova, S.Perrey, N.Marx, D.Bacqueville, and J.Plutzky (2002).
Peroxisome proliferator-activated receptors.
  Curr Atheroscler Rep, 4, 59-64.  
12354121 T.Ostberg, G.Bertilsson, L.Jendeberg, A.Berkenstam, and J.Uppenberg (2002).
Identification of residues in the PXR ligand binding domain critical for species specific and constitutive activation.
  Eur J Biochem, 269, 4896-4904.  
11340063 A.C.Steinmetz, J.P.Renaud, and D.Moras (2001).
Binding of ligands and activation of transcription by nuclear receptors.
  Annu Rev Biophys Biomol Struct, 30, 329-359.  
11698662 H.E.Xu, M.H.Lambert, V.G.Montana, K.D.Plunket, L.B.Moore, J.L.Collins, J.A.Oplinger, S.A.Kliewer, R.T.Gampe, D.D.McKee, J.T.Moore, and T.M.Willson (2001).
Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors.
  Proc Natl Acad Sci U S A, 98, 13919-13924.
PDB codes: 1k74 1k7l
11353326 I.P.Torra, G.Chinetti, C.Duval, J.C.Fruchart, and B.Staels (2001).
Peroxisome proliferator-activated receptors: from transcriptional control to clinical practice.
  Curr Opin Lipidol, 12, 245-254.  
11561170 J.Plutzky (2001).
Peroxisome proliferator-activated receptors in endothelial cell biology.
  Curr Opin Lipidol, 12, 511-518.  
11395411 T.M.Willson, M.H.Lambert, and S.A.Kliewer (2001).
Peroxisome proliferator-activated receptor gamma and metabolic disease.
  Annu Rev Biochem, 70, 341-367.  
11607933 U.Egner, N.Heinrich, M.Ruff, M.Gangloff, A.Mueller-Fahrnow, and J.M.Wurtz (2001).
Different ligands-different receptor conformations: modeling of the hER alpha LBD in complex with agonists and antagonists.
  Med Res Rev, 21, 523-539.  
11358696 Y.Shi, and J.T.Koh (2001).
Selective regulation of gene expression by an orthogonal estrogen receptor-ligand pair created by polar-group exchange.
  Chem Biol, 8, 501-510.  
10862523 A.Sapone, J.M.Peters, S.Sakai, S.Tomita, S.S.Papiha, R.Dai, F.K.Friedman, and F.J.Gonzalez (2000).
The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants.
  Pharmacogenetics, 10, 321-333.  
10696077 D.Bishop-Bailey (2000).
Peroxisome proliferator-activated receptors in the cardiovascular system.
  Br J Pharmacol, 129, 823-834.  
10940341 D.Hwang (2000).
Fatty acids and immune responses--a new perspective in searching for clues to mechanism.
  Annu Rev Nutr, 20, 431-456.  
10836145 J.C.Corton, S.P.Anderson, and A.Stauber (2000).
Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators.
  Annu Rev Pharmacol Toxicol, 40, 491-518.  
10845098 J.Zhang, and M.A.Lazar (2000).
The mechanism of action of thyroid hormones.
  Annu Rev Physiol, 62, 439-466.  
10677485 K.Yamamoto, H.Masuno, M.Choi, K.Nakashima, T.Taga, H.Ooizumi, K.Umesono, W.Sicinska, J.VanHooke, H.F.DeLuca, and S.Yamada (2000).
Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain.
  Proc Natl Acad Sci U S A, 97, 1467-1472.  
11015194 N.Swamy, W.Xu, N.Paz, J.C.Hsieh, M.R.Haussler, G.J.Maalouf, S.C.Mohr, and R.Ray (2000).
Molecular modeling, affinity labeling, and site-directed mutagenesis define the key points of interaction between the ligand-binding domain of the vitamin D nuclear receptor and 1 alpha,25-dihydroxyvitamin D3.
  Biochemistry, 39, 12162-12171.  
10782092 P.Barnett, H.F.Tabak, and E.H.Hettema (2000).
Nuclear receptors arose from pre-existing protein modules during evolution.
  Trends Biochem Sci, 25, 227-228.  
10983973 P.Pissios, I.Tzameli, P.Kushner, and D.D.Moore (2000).
Dynamic stabilization of nuclear receptor ligand binding domains by hormone or corepressor binding.
  Mol Cell, 6, 245-253.  
10882139 R.T.Gampe, V.G.Montana, M.H.Lambert, A.B.Miller, R.K.Bledsoe, M.V.Milburn, S.A.Kliewer, T.M.Willson, and H.E.Xu (2000).
Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors.
  Mol Cell, 5, 545-555.
PDB codes: 1fm6 1fm9
11050318 W.Bourguet, P.Germain, and H.Gronemeyer (2000).
Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.
  Trends Pharmacol Sci, 21, 381-388.  
10600690 A.Mueller-Fahrnow, and U.Egner (1999).
Ligand-binding domain of estrogen receptors.
  Curr Opin Biotechnol, 10, 550-556.  
  10454590 J.Zhang, X.Hu, and M.A.Lazar (1999).
A novel role for helix 12 of retinoid X receptor in regulating repression.
  Mol Cell Biol, 19, 6448-6457.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.