Crystal structures of the ligand-binding domain of human peroxisome proliferator-activated receptor δ in complexes with phenylpropanoic acid derivatives and a pyridine carboxylic acid derivative

Abstract

Peroxisome proliferator-activated receptor δ (PPARδ) is a member of the nuclear receptor family and regulates glucose and lipid homeostasis in a ligand-dependent manner. Numerous phenylpropanoic acid derivatives targeting three PPAR subtypes (PPARα, PPARγ and PPARδ) have been developed towards the treatment of serious diseases such as lipid-metabolism disorders. In spite of the increasing attraction of PPARδ as a pharmaceutical target, only a limited number of protein-ligand complex structures are available. Here, four crystal structures of the ligand-binding domain of PPARδ in complexes with phenylpropanoic acid derivatives and a pyridine carboxylic acid derivative are described, including an updated, higher resolution version of a previous studied structure and three novel structures. These structures showed that the ligands were bound in the ligand-binding pocket of the receptor in a similar manner but with minor variations. The results could provide variable structural information for the further design and development of ligands targeting PPARδ.

Keywords: PPARδ; ligand-binding domain; nuclear receptors; peroxisome proliferator-activated receptor δ.

Figure 1

(a) A schematic diagram of the ligand-activated PPARδ–RXRα heterodimer. (b) Chemical structures of the ligands used in this study. Functional units are shown on the KCL structure with the binding arms in the ligand-binding pocket of PPARδ.

Figure 2

Structures of PPARδ LBD–ligand complexes. (a) Overall view of the complexes. PPARδ LDB is shown as a ribbon representation colored from blue (N-­terminus) to red (C-terminus). Omit F _o − F _c electron-density maps for (b) TIPP-204, (c) JKPL38, (d) JKPL39 and (e) JK122 are shown contoured at 3.0σ. Ligands are shown as stick models. C atoms of TIPP-204, JKPL38, JKPL39 and JK122 are colored yellow, cyan, green and violet, respectively. All atomic models were generated by PyMOL (http://www.pymol.org).

Figure 3

Ligand binding to PPARδ LBD. (a) Structure of PPARδ LBD–TIPP-204. A comparison is shown of the previous (gray) and current high-resolution (yellow) structures. Different conformations are indicated by arrows. (b) Superposition of PPARδ LBD in complexes with TIPP-204 (yellow), JKPL38 (cyan) and JKPL39 (green). The arm 2 groove is represented by a transparent surface. An arrow indicates the bottom of arm 2. (c) Structure comparison of PPARδ LBD–TIPP-204 (yellow) and PPARδ LBD–JK122 (violet). The branch butoxy residue and the tail trifluoromethylbenzyl residue shift slightly (about 0.8 Å) towards arms 2 and 3, respectively, compared with the corresponding parts of TIPP-204 (indicated by arrows).