6D3E

PPARg LBD in Complex with SR1988

Summary for 6D3E

• Entry DOI: 10.2210/pdb6d3e/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, 1-[(2,4-difluorophenyl)methyl]-2,3-dimethyl-N-[(1R)-1-phenylpropyl]-1H-indole-5-carboxamide (3 entities in total)
• Functional Keywords: type 2 diabetes, nuclear receptor, drug discovery, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 64584.88

Authors

Frkic, R.L.,Bruning, J.B. (deposition date: 2018-04-15, release date: 2019-02-27, Last modification date: 2023-10-04)

Primary citation

Frkic, R.L.,Chua, B.S.,Shin, Y.,Pascal, B.D.,Novick, S.J.,Kamenecka, T.M.,Griffin, P.R.,Bruning, J.B.
Structural and Dynamic Elucidation of a Non-acid PPARgammaPartial Agonist: SR1988.
Nucl Receptor Res, 5:-, 2018

PubMed Abstract: Targeting peroxisome proliferator-activated receptor (PPAR) 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 PPAR 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 PPAR by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.

PubMed: 30906767
DOI: 10.11131/2018/101350

Experimental method

X-RAY DIFFRACTION (2.395 Å)