PPAR Isotype-Selective Ligands

The structure of the FA eicosapentaenoic acid (EPA) bound to PPAR-d has been determined (PDB entry 3GWX) [35]. The ligand-binding pocket of PPAR-d assumes roughly a Y shape with each of the three arms approximately 12 A in length. One arm of the Y is composed of a mix of hydrophobic residues and polar residues and is capped by two residues from helix-12. This is the only arm of the Y that is substantially polar in character. Another arm of the Y is composed of hydrophobic residues and is sealed by the last residue of helix-1, and the loop between helices-1 and -2. The third arm of the Y-shaped pocket is composed mainly of hydrophobic residues with a few polar residues. The interior of the ligand-binding pocket is accessible via a channel that is exposed to solvent [35] 

The EPA complex crystal has two molecules in the asymmetric unit each independent molecule has two distinct conformations for the EPA ligand (Fig. 1.29). 

I 7 Molecular Recognition of Nuclear Hormone Receptor-Ligand Complexes 

Y makes polar interactions with the carboxylate head group of the ligand, the interactions in the other two arms are mostly hydrophobic. 

A close analogue of farglitazar, GW409544, is also a co-agonist that binds only ten times poorer towards PPAR-a (Fig. 1.35). Neither farglitazar nor GW409544 bind to, or activate, PPAR- to any measurable extent. The structures of 

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