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Type: Journal article
Title: Structural and dynamic elucidation of a non-acid PPARγ partial agonist: SR1988
Author: Frkic, R.L.
Chua, B.S.
Shin, Y.
Pascal, B.D.
Novick, S.J.
Kamenecka, T.M.
Griffin, P.R.
Bruning, J.B.
Citation: Nuclear Receptor Research, 2018; 5:101350-1-101350-12
Publisher: KenzPub
Issue Date: 2018
ISSN: 2314-5706
Statement of
Rebecca L. Frkic, Benjamin S. Chua, Youseung Shin, Bruce D. Pasca, Scott J. Novick, Theodore M. Kamenecka, Patrick R. Griffin, and John B. Bruning
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.
Keywords: HDX
nuclear receptor
partial agonist
type 2 diabetes
Rights: Copyright © 2018 Rebecca L. Frkic et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI: 10.11131/2018/101350
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