PDBsum entry 1i7g

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Transcription PDB id
Protein chain
259 a.a. *
Waters ×70
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Crystal structure of the ligand binding domain from human ppar-alpha in complex with the agonist az 242
Structure: Peroxisome proliferator activated receptor alpha. Chain: a. Fragment: ligand binding domain. Synonym: ppar-alpha. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
2.20Å     R-factor:   0.237     R-free:   0.271
Authors: J.F.W.Petersen,P.Cronet,R.Folmer,N.Blomberg,K.Sjoblom, U.Karlsson,E.-L.Lindstedt,K.Bamberg
Key ref:
P.Cronet et al. (2001). Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family. Structure, 9, 699-706. PubMed id: 11587644 DOI: 10.1016/S0969-2126(01)00634-7
09-Mar-01     Release date:   09-Mar-02    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
Q07869  (PPARA_HUMAN) -  Peroxisome proliferator-activated receptor alpha
468 a.a.
259 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 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: 10.1016/S0969-2126(01)00634-7 Structure 9:699-706 (2001)
PubMed id: 11587644  
Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family.
P.Cronet, J.F.Petersen, R.Folmer, N.Blomberg, K.Sjöblom, U.Karlsson, E.L.Lindstedt, K.Bamberg.
BACKGROUND: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPARalpha in fatty acid oxidation and PPARgamma in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPARalpha ligand binding domain structure. RESULTS: We have solved the crystal structure of the PPARalpha ligand binding domain (LBD) in complex with the combined PPARalpha and -gamma agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPARgamma_LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPARalpha and -gamma subtypes. Heteronuclear NMR data on PPARalpha in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPARalpha/AZ 242 complex with the PPARgamma/AZ 242 complex and previously solved PPARgamma structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix. CONCLUSIONS: The complex of PPARalpha and PPARgamma with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design.
  Selected figure(s)  
Figure 2.
Figure 2. General Structural Features(a) An overall schematic representation of the hPPARa_LBD structure. The ligand (AZ 242) is shown as a stick model (red). The detergent (DBC) used for crystallization is represented in cyan. The residues immediately adjacent to the regions excluded from the model are indicated by their numbers, and helices are labeled H1-H12. The AF2 helix is labeled.(b) sA-weighted F[o]-F[c] electron density omit map calculated around AZ 242. Residues forming hydrophobic contacts with AZ 242 are represented in green, and the residue forming the hydrogen bonds with the propionic head group are represented in blue.(c) A stereo view of a superposition of hPPARg_LBD (red) and hPPARd_LBD (yellow) on hPPARa_LBD (blue). Only the Ca trace is shown. Ligands from the three respective structures are shown in green. The central cavity is marked with a "C", and the upper distal and lower distal cavities are marked with an "U" and "L", respectively

  The above figure is reprinted by permission from Cell Press: Structure (2001, 9, 699-706) copyright 2001.  
  Figure was selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21414824 F.Lannutti, A.Marrone, and N.Re (2011).
Prediction of the PPARα agonism of fibrates by combined MM-docking approaches.
  J Mol Graph Model, 29, 865-875.  
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.  
  20936127 M.Rakhshandehroo, B.Knoch, M.Müller, and S.Kersten (2010).
Peroxisome proliferator-activated receptor alpha target genes.
  PPAR Res, 2010, 0.  
20830700 S.L.Regan, J.L.Maggs, T.G.Hammond, C.Lambert, D.P.Williams, and B.K.Park (2010).
Acyl glucuronides: the good, the bad and the ugly.
  Biopharm Drug Dispos, 31, 367-395.  
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.  
20414453 S.R.Pyper, N.Viswakarma, S.Yu, and J.K.Reddy (2010).
PPARalpha: energy combustion, hypolipidemia, inflammation and cancer.
  Nucl Recept Signal, 8, e002.  
20717101 T.Waku, T.Shiraki, T.Oyama, K.Maebara, R.Nakamori, and K.Morikawa (2010).
The nuclear receptor PPARγ individually responds to serotonin- and fatty acid-metabolites.
  EMBO J, 29, 3395-3407.
PDB codes: 2zk6 3ads 3adt 3adu 3adv 3adw 3adx
  19435785 A.N.Simpkins, R.D.Rudic, D.A.Schreihofer, S.Roy, M.Manhiani, H.J.Tsai, B.D.Hammock, and J.D.Imig (2009).
Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection.
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19757405 J.Lu, M.I.Dawson, Q.Y.Hu, Z.Xia, J.D.Dambacher, M.Ye, X.K.Zhang, and E.Li (2009).
The effect of antagonists on the conformational exchange of the retinoid X receptor alpha ligand-binding domain.
  Magn Reson Chem, 47, 1071-1080.  
19622862 T.Oyama, K.Toyota, T.Waku, Y.Hirakawa, N.Nagasawa, J.I.Kasuga, Y.Hashimoto, H.Miyachi, and K.Morikawa (2009).
Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures.
  Acta Crystallogr D Biol Crystallogr, 65, 786-795.
PDB codes: 2znn 2zno 2znp 2znq
19326383 U.Grether, A.Bénardeau, J.Benz, A.Binggeli, D.Blum, H.Hilpert, B.Kuhn, H.P.Märki, M.Meyer, P.Mohr, K.Püntener, S.Raab, A.Ruf, and D.Schlatter (2009).
Design and biological evaluation of novel, balanced dual PPARalpha/gamma agonists.
  ChemMedChem, 4, 951-956.
PDB codes: 3fei 3fej
19067454 Y.Tanrikulu, O.Rau, O.Schwarz, E.Proschak, K.Siems, L.Müller-Kuhrt, M.Schubert-Zsilavecz, and G.Schneider (2009).
Structure-based pharmacophore screening for natural-product-derived PPARgamma agonists.
  Chembiochem, 10, 75-78.  
19079281 C.Casals-Casas, J.N.Feige, and B.Desvergne (2008).
Interference of pollutants with PPARs: endocrine disruption meets metabolism.
  Int J Obes (Lond), 32, S53-S61.  
18406164 D.B.Magner, and A.Antebi (2008).
Caenorhabditis elegans nuclear receptors: insights into life traits.
  Trends Endocrinol Metab, 19, 153-160.  
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.  
18055466 H.A.Hostetler, H.Huang, A.B.Kier, and F.Schroeder (2008).
Glucose Directly Links to Lipid Metabolism through High Affinity Interaction with Peroxisome Proliferator-activated Receptor {alpha}.
  J Biol Chem, 283, 2246-2254.  
17980149 J.Lu, M.Chen, S.E.Stanley, and E.Li (2008).
Effect of heterodimer partner RXRalpha on PPARgamma activation function-2 helix in solution.
  Biochem Biophys Res Commun, 365, 42-46.  
18355413 O.A.Gani (2008).
Are fish oil omega-3 long-chain fatty acids and their derivatives peroxisome proliferator-activated receptor agonists?
  Cardiovasc Diabetol, 7, 6.  
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.  
17963209 O.Rau, H.Zettl, L.Popescu, D.Steinhilber, and M.Schubert-Zsilavecz (2008).
The treatment of dyslipidemia--what's left in the pipeline?
  ChemMedChem, 3, 206-221.  
18193404 T.Itoh, and K.Yamamoto (2008).
Peroxisome proliferator activated receptor gamma and oxidized docosahexaenoic acids as new class of ligand.
  Naunyn Schmiedebergs Arch Pharmacol, 377, 541-547.  
19172745 T.Itoh, L.Fairall, K.Amin, Y.Inaba, A.Szanto, B.L.Balint, L.Nagy, K.Yamamoto, and J.W.Schwabe (2008).
Structural basis for the activation of PPARgamma by oxidized fatty acids.
  Nat Struct Mol Biol, 15, 924-931.
PDB codes: 2vsr 2vst 2vv0 2vv1 2vv2 2vv3 2vv4
17462987 A.L.Ambrosio, S.M.Dias, I.Polikarpov, R.B.Zurier, S.H.Burstein, and R.C.Garratt (2007).
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 282, 18625-18633.
PDB code: 2om9
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.  
17403688 G.Pochetti, C.Godio, N.Mitro, D.Caruso, A.Galmozzi, S.Scurati, F.Loiodice, G.Fracchiolla, P.Tortorella, A.Laghezza, A.Lavecchia, E.Novellino, F.Mazza, and M.Crestani (2007).
Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands.
  J Biol Chem, 282, 17314-17324.
PDB codes: 2i4j 2i4p 2i4z
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
17468099 J.N.Feige, L.Gelman, D.Rossi, V.Zoete, R.Métivier, C.Tudor, S.I.Anghel, A.Grosdidier, C.Lathion, Y.Engelborghs, O.Michielin, W.Wahli, and B.Desvergne (2007).
The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.
  J Biol Chem, 282, 19152-19166.  
17200111 L.Michalik, V.Zoete, G.Krey, A.Grosdidier, L.Gelman, P.Chodanowski, J.N.Feige, B.Desvergne, W.Wahli, and O.Michielin (2007).
Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.
  J Biol Chem, 282, 9666-9677.  
16841235 G.Carta, V.Onnis, A.J.Knox, D.Fayne, and D.G.Lloyd (2006).
Permuting input for more effective sampling of 3D conformer space.
  J Comput Aided Mol Des, 20, 179-190.  
16768463 H.A.Hostetler, A.B.Kier, and F.Schroeder (2006).
Very-long-chain and branched-chain fatty acyl-CoAs are high affinity ligands for the peroxisome proliferator-activated receptor alpha (PPARalpha).
  Biochemistry, 45, 7669-7681.  
16511589 P.Lefebvre, G.Chinetti, J.C.Fruchart, and B.Staels (2006).
Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.
  J Clin Invest, 116, 571-580.  
16917105 V.Y.Ng, C.Morisseau, J.R.Falck, B.D.Hammock, and D.L.Kroetz (2006).
Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor alpha-dependent repression of cyclin D1.
  Arterioscler Thromb Vasc Biol, 26, 2462-2468.  
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.  
16188170 C.J.Bailey (2005).
Drugs on the horizon for diabesity.
  Curr Diab Rep, 5, 353-359.  
16149734 F.Schroeder, H.Huang, H.A.Hostetler, A.D.Petrescu, R.Hertz, J.Bar-Tana, and A.B.Kier (2005).
Stability of fatty acyl-coenzyme A thioester ligands of hepatocyte nuclear factor-4alpha and peroxisome proliferator-activated receptor-alpha.
  Lipids, 40, 559-568.  
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
15825830 L.N.Larsen, L.Granlund, A.K.Holmeide, L.Skattebøl, H.I.Nebb, and J.Bremer (2005).
Sulfur-substituted and alpha-methylated fatty acids as peroxisome proliferator-activated receptor activators.
  Lipids, 40, 49-57.  
15695504 T.Shiraki, N.Kamiya, S.Shiki, T.S.Kodama, A.Kakizuka, and H.Jingami (2005).
Alpha,beta-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 280, 14145-14153.  
15271292 A.L.Parrill, V.M.Sardar, and H.Yuan (2004).
Sphingosine 1-phosphate and lysophosphatidic acid receptors: agonist and antagonist binding and progress toward development of receptor-specific ligands.
  Semin Cell Dev Biol, 15, 467-476.  
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.  
15516807 H.Miyachi (2004).
[Design and synthesis of subtype- and species-selective peroxisome proliferator-activated receptor (PPAR) alpha ligands]
  Yakugaku Zasshi, 124, 803-813.  
15258145 T.Ostberg, S.Svensson, G.Selén, J.Uppenberg, M.Thor, M.Sundbom, M.Sydow-Bäckman, A.L.Gustavsson, and L.Jendeberg (2004).
A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects.
  J Biol Chem, 279, 41124-41130.
PDB code: 1wm0
12943493 A.R.Miller, and G.J.Etgen (2003).
Novel peroxisome proliferator-activated receptor ligands for Type 2 diabetes and the metabolic syndrome.
  Expert Opin Investig Drugs, 12, 1489-1500.  
12536206 B.C.Kallenberger, J.D.Love, V.K.Chatterjee, and J.W.Schwabe (2003).
A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease.
  Nat Struct Biol, 10, 136-140.  
12163127 H.Vosper, G.A.Khoudoli, T.L.Graham, and C.N.Palmer (2002).
Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis.
  Pharmacol Ther, 95, 47-62.  
12079620 J.Berger, and J.A.Wagner (2002).
Physiological and therapeutic roles of peroxisome proliferator-activated receptors.
  Diabetes Technol Ther, 4, 163-174.  
11606578 C.J.Sinal, M.Yoon, and F.J.Gonzalez (2001).
Antagonism of the actions of peroxisome proliferator-activated receptor-alpha by bile acids.
  J Biol Chem, 276, 47154-47162.  
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