6FZY

PPAR mutant

6FZY の概要

• エントリーDOI: 10.2210/pdb6fzy/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma (2 entities in total)
• 機能のキーワード: nuclear receptor, 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: 63786.17

構造登録者

Rochel, N. (登録日: 2018-03-15, 公開日: 2019-02-13, 最終更新日: 2024-05-08)

主引用文献

Rochel, N.,Krucker, C.,Coutos-Thevenot, L.,Osz, J.,Zhang, R.,Guyon, E.,Zita, W.,Vanthong, S.,Hernandez, O.A.,Bourguet, M.,Badawy, K.A.,Dufour, F.,Peluso-Iltis, C.,Heckler-Beji, S.,Dejaegere, A.,Kamoun, A.,de Reynies, A.,Neuzillet, Y.,Rebouissou, S.,Beraud, C.,Lang, H.,Massfelder, T.,Allory, Y.,Cianferani, S.,Stote, R.H.,Radvanyi, F.,Bernard-Pierrot, I.
Recurrent activating mutations of PPAR gamma associated with luminal bladder tumors.
Nat Commun, 10:253-253, 2019

PubMed Abstract: The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.

PubMed: 30651555
DOI: 10.1038/s41467-018-08157-y

実験手法

X-RAY DIFFRACTION (3.1 Å)