PDBsum entry 4prg

Receptor

PDB id: 4prg

Contents

Protein chain

270 a.a. *

Ligands

072 ×4

* Residue conservation analysis

PDB id:

4prg

Name:

Receptor

Title:

0072 partial agonist ppar gamma cocrystal

Structure:

Protein (peroxisome proliferator activated receptor gamma). Chain: a, b, c, d. Fragment: ligand binding domain, residues 207-476. Engineered: yes. Other_details: 0072 partial agonist cocrystal

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hppargamma. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: plasmid is prset a

Biol. unit:

Dimer (from PQS)

Resolution:

2.90Å R-factor: 0.240 R-free: 0.283

Authors:

M.V.Milburn

Key ref:

J.L.Oberfield et al. (1999). A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci U S A, 96, 6102-6106. PubMed id: 10339548 DOI: 10.1073/pnas.96.11.6102

Date:

07-May-99 Release date: 27-May-99

Protein chains

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

Seq: 505 a.a.

Struc: 270 a.a.

DOI no: 10.1073/pnas.96.11.6102

Proc Natl Acad Sci U S A 96:6102-6106 (1999)

PubMed id: 10339548

A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.

J.L.Oberfield, J.L.Collins, C.P.Holmes, D.M.Goreham, J.P.Cooper, J.E.Cobb, J.M.Lenhard, E.A.Hull-Ryde, C.P.Mohr, S.G.Blanchard, D.J.Parks, L.B.Moore, J.M.Lehmann, K.Plunket, A.B.Miller, M.V.Milburn, S.A.Kliewer, T.M.Willson.

ABSTRACT

The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.

Selected figure(s)

Figure 2.
Fig. 2. GW0072 is a PPAR ligand with a unique functional profile. (A) Dose response on the PPAR -GAL4 chimera for GW0072 ( circle ) and GW0072 plus 100 nM rosiglitazone ( ). Reporter activity was expressed as the % of the maximal activation by 1 µM rosiglitazone. GW0072 demonstrates competitive antagonism of rosiglitazone but retains weak agonist activity at µM concentrations. (B) Activity on full-length PPAR 2 for 100 nM rosiglitazone (TZD), 10 µM GW0072 (GW), and 100 nM rosiglitazone plus 10 µM GW0072 (TZD + GW). Vehicle was 0.1% DMSO. Reporter activity was expressed as the % of the maximal activation by 1 µM rosiglitazone. (C-F) The functional activity of GW0072 is paralleled by its effects on coactivator recruitment to PPAR 2 in a mammalian two-hybrid assay. GW0072 (GW) (10 µM) antagonizes recruitment of the coactivators CBP and SRC1 promoted by 1 µM rosiglitazone (TZD). GW0072 (GW) (10 µM) does not recruit the corepressors NCoR or SMRT.

Figure 4.
Fig. 4. GW0072 defines an additional class of nuclear receptor ligands. Agonist ligands (gray) shift the AF-2 helix (yellow) into a position that stabilizes recruitment of coactivator (green) to the receptor ligand-binding domain (white). Antagonist ligands (gray) bind to the receptor by using the same epitopes, but their larger size shifts the AF-2 helix into a position that displaces the coactivator. Antagonist ligands also recruit corepressor (red) to the receptor ligand-binding domain. The partial agonist GW0072 (gray) binds to its receptor by using different epitopes, such that it does not directly interact with the AF-2 helix.

Figures were selected by an automated process.