6D3E

PPARg LBD in Complex with SR1988

6D3E の概要

• エントリーDOI: 10.2210/pdb6d3e/pdb
• 分子名称: 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)
• 機能のキーワード: type 2 diabetes, nuclear receptor, drug discovery, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64584.88

構造登録者

Frkic, R.L.,Bruning, J.B. (登録日: 2018-04-15, 公開日: 2019-02-27, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.395 Å)