PDBsum entry 2i4z

Transcription

PDB id: 2i4z

Contents

Protein chain

270 a.a. *

Ligands

DRH

Waters ×195

* Residue conservation analysis

PDB id:

2i4z

Name:

Transcription

Title:

Crystal structure of the complex between ppargamma and the partial agonist lt127 (ureidofibrate derivative). This structure has been obtained from crystals soaked for 6 hours.

Structure:

Peroxisome proliferator-activated receptor gamma. Chain: a, b. Fragment: ligand binding domain (lbd), residues 223-504. Synonym: ppar-gamma. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pparg, nr1c3. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.25Å R-factor: 0.238 R-free: 0.290

Authors:

G.Pochetti,F.Mazza

Key ref:

G.Pochetti et al. (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. PubMed id: 17403688 DOI: 10.1074/jbc.M702316200

Date:

23-Aug-06 Release date: 17-Apr-07

Protein chains

P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma from Homo sapiens

Seq: 505 a.a.

Struc: 270 a.a.

DOI no: 10.1074/jbc.M702316200

J Biol Chem 282:17314-17324 (2007)

PubMed id: 17403688

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.

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, M.Crestani.

ABSTRACT

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also targets of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate-like derivatives. In particular, we show that the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the S-enantiomer, (S)-1, is a less potent partial agonist. Most importantly, we report the x-ray crystal structures of the PPARgamma ligand binding domain complexed with the R- and the S-enantiomer, respectively. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behavior as full or partial agonist. Another crystal structure of the PPARgamma.(S)-1 complex, only differing in the soaking time of the ligand, is also presented. The comparison of the two structures of the complexes with the partial agonist reveals significant differences and is suggestive of the possible coexistence in solution of transcriptionally active and inactive forms of helix 12 in the presence of a partial agonist. Mutation analysis confirms the importance of Leu(465), Leu(469), and Ile(472) in the activation by (R)-1 and underscores the key role of Gln(286) in the PPARgamma activity.

Selected figure(s)

Figure 7.
FIGURE 7. C^ superposition of the complexes with the R- and the S-enantiomer (in yellow and cyan, respectively). Protein side chains of the complex with the R-enantiomer are shown in green; the correspondent side-chains are in pink for the complex with the S-enantiomer.

Figure 11.
FIGURE 11. Superposition of the C^ traces of the complexes of PPAR with the R-enantiomer (green), the S-enantiomer (cyan), and rosiglitazone (purple). Putative contacts are shown in parentheses.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 17314-17324) copyright 2007.

Figures were selected by the author.