Structural review of PPARγ in complex with ligands: Cartesian- and dihedral angle principal component analyses of X-ray crystallographic data

Abstract

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.

Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ

“…We also started apo aMD simulations with helix 12 in an alternate crystal contact induced conformation 45 , which we refer to as the inactive structure. This conformation is very different from the canonical active conformation; the helical axis of this inactive helix 12 conformation is nearly orthogonal to the active axis (Supplementary Fig.…”

International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023

“…Crystal structures showed that the conformation of helix 12 is different when bound to a corepressor (SMRT) (H. E. Xu et al, 2002) versus a coactivator (e.g., SRC1) (Nolte et al, 1998). Surprisingly, crystal structures of PPARγ bound to full agonists, antagonists, and inverse agonists are remarkably similar (Kaupang, Laitinen, Poso, & Hansen, 2017). In contrast, solution state methods, including protein and fluorine NMR, simulation, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and fluorescence anisotropy demonstrate that ligands have dramatic and varied effects on the structural state of PPAR (J.…”