Abstract
Targeting peroxisome proliferator-activated receptor γ (PPARγ) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPARγ by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPARγ by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.
Highlights
peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-modulated transcription factor belonging to the nuclear receptor superfamily
The pharmacokinetic liabilities of PPARγ ligands with acid moieties has prompted the investigation of ligands designed to bind PPARγ with high affinity without acidic properties
Our previously reported non-acid partial agonist SR2067 displayed reduced transactivation of PPARγ while still maintaining high potency binding to the receptor [13]
Summary
PPARγ is a ligand-modulated transcription factor belonging to the nuclear receptor superfamily. It forms a heterodimer with retinoid X receptor α (RXRα) to play key roles in metabolism and the maintenance of glucose homeostasis through modulating numerous target genes [1, 2]. Sequence analysis and crystallographic studies reveal that PPARγ displays the conserved nuclear receptor domain architecture, comprising of the activation function 1 domain essential for ligand-independent coregulator binding, a DNA binding domain (DBD), a hinge region, and a ligand binding domain (LBD). The LBD binds a number of endogenous ligands, as well as facilitating dimerisation with RXRα, and contains a regulatory activation function 2 (AF2) region which binds coregulators in a ligand-dependant manner [3].
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