Two decades of research into the ligand-dependent modulation of the activity of the peroxisome proliferator-activated receptor γ (PPARγ) have demonstrated the heterogeneous modes of action of PPARγ ligands, in terms of their interaction surfaces in the ligand-binding pocket, binding stoichiometry and ability to interact with functionally important parts of the receptor, through both direct and allosteric mechanisms. These findings signal the complex mechanistic bases of the distinct biological effects of different classes of PPARγ ligands. Today, the development of PPARγ ligands focuses on partial- and non-agonists as opposed to classical agonists, due to the severe side effects observed with PPARγ classical agonists as therapeutic agents. To aid this development, we performed principal component analyses of the atomic (Cartesian) coordinates (cPCA) and dihedral angles (dPCA) of the structures of human PPARγ from X-ray crystallography, available in the public domain, seeking to reveal ligand-induced trends. In the cPCA, projections of the structures along the principal components (PCs) demonstrated a moderate correlation between cPC1 and structural parameters related to the stabilization of helix 12, which is central to the transcriptional activation by PPARγ classical agonists. Consequently, the presented cPCA mapping of the PPARγ-ligand complexes may guide in silico drug discovery programs seeking to avoid stabilization of helix 12 in their development of partial- and non-agonistic PPARγ ligands. Notably, while the dPCA could identify key regions of dihedral fluctuation in the structural ensemble, the distributions along dPC1 - 2 could not be classified according to the same parameters as the distribution along cPC1. Proteins 2017; 85:1684-1698. © 2017 Wiley Periodicals, Inc.