Sequential Backbone Assignment of Peroxisome Proliferator-Activated Receptor-γ Ligand Binding Domain

Riepl, Hubert; Hartl, Rainer; Bauer, Margit; Nar, Herbert; Kauschke, Stefan G.; Kalbitzer, Hans Robert; Maurer, Till

doi:10.1007/s10858-005-7556-1

Cited by 3 publications

(4 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using additional NMR data and other assignments 16 , we extended PPARγ NMR chemical shift assignments for MRL20 and MRL24 12 in the following regions: H2′-H3, β-sheet region and loops, the Ω loop (a flexible loop region comprising ∼15 residues between H2′ and H3 spanning D260-K275), H11 and H12. Titration of MRL20 up to 1:1 (ligand:protein) reveals a transition in slow exchange on the NMR time scale (Fig.…”

Section: Resultsmentioning

confidence: 99%

An alternate binding site for PPARγ ligands

et al. 2014

View full text Add to dashboard Cite

PPARγ is a target for insulin sensitizing drugs such as glitazones, which improve plasma glucose maintenance in patients with diabetes. Synthetic ligands have been designed to mimic endogenous ligand binding to a canonical ligand-binding pocket to hyperactivate PPARγ. Here we reveal that synthetic PPARγ ligands also bind to an alternate site, leading to unique receptor conformational changes that impact coregulator binding, transactivation and target gene expression. Using structure-function studies we show that alternate site binding occurs at pharmacologically relevant ligand concentrations, and is neither blocked by covalently bound synthetic antagonists nor by endogenous ligands indicating non-overlapping binding with the canonical pocket. Alternate site binding likely contributes to PPARγ hyperactivation in vivo, perhaps explaining why PPARγ full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPARγ activation by ligands and suggest that allosteric modulators could be designed to fine tune PPARγ activity without competing with endogenous ligands.

show abstract

Section: Resultsmentioning

confidence: 99%

An alternate binding site for PPARγ ligands

et al. 2014

View full text Add to dashboard Cite

show abstract

“…observed two distinct amide N‐H chemical shifts for Tyr473 . Several NMR studies have also found that a large number of crosspeaks missing from the spectra of apo‐PPARγ, are partially to fully restored upon addition of a ligand . These findings attest to apo‐PPARγ being a highly mobile structure in solution, whose conformational space is focused upon ligand binding.…”

Section: Resultsmentioning

confidence: 88%

“…The origin of the type B chains, which are frequently more poorly resolved in the 16 Several NMR studies have also found that a large number of crosspeaks missing from the spectra of apo-PPARg, are partially to fully restored upon addition of a ligand. 10,16,41,42 These findings attest to apo-PPARg being a highly mobile structure in solution, whose conformational space is focused upon ligand binding. Both the larger conformational freedom of helix 12 in apo-PPARg, as well as helix 12 conformations similar to those observed by X-ray crystallography in the type A and type B chains [ Fig.…”

Section: Initial Analyses Of the Datasetmentioning

confidence: 99%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

“…Considering LBD conformational dynamics, ligand binding leads to changes in the conformational populations of the LBD, as observed by nuclear magnetic resonance (NMR) spectroscopy [68,86,87,97,[107][108][109][110][111], hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) [ [86,87,96,118,119]. In PPARγ, analyses of such structural ensembles have demonstrated that the large conformational diversity observed in apo-PPARγ, in particu-lar that of H12, is strongly reduced upon interaction with classical agonists.…”

Section: Classical Ppar Agonism Antagonism and Beyondmentioning

confidence: 99%

The PPARΩPocket: Renewed Opportunities for Drug Development

Kaupang

Hansen

2020

PPAR Research

View full text Add to dashboard Cite

The past decade of PPARγ research has dramatically improved our understanding of the structural and mechanistic bases for the diverging physiological effects of different classes of PPARγ ligands. The discoveries that lie at the heart of these developments have enabled the design of a new class of PPARγ ligands, capable of isolating central therapeutic effects of PPARγ modulation, while displaying markedly lower toxicities than previous generations of PPARγ ligands. This review examines the emerging framework around the design of these ligands and seeks to unite its principles with the development of new classes of ligands for PPARα and PPARβ/δ. The focus is on the relationships between the binding modes of ligands, their influence on PPAR posttranslational modifications, and gene expression patterns. Specifically, we encourage the design and study of ligands that primarily bind to the Ω pockets of PPARα and PPARβ/δ. In support of this development, we highlight already reported ligands that if studied in the context of this new framework may further our understanding of the gene programs regulated by PPARα and PPARβ/δ. Moreover, recently developed pharmacological tools that can be utilized in the search for ligands with new binding modes are also presented.

show abstract

Sequential Backbone Assignment of Peroxisome Proliferator-Activated Receptor-γ Ligand Binding Domain

Cited by 3 publications

References 1 publication

An alternate binding site for PPARγ ligands

An alternate binding site for PPARγ ligands

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

The PPARΩPocket: Renewed Opportunities for Drug Development

Contact Info

Product

Resources

About