5M24

RARg mutant-S371E

5M24 の概要

• エントリーDOI: 10.2210/pdb5m24/pdb
• 分子名称: Retinoic acid receptor gamma, (9cis)-retinoic acid, DODECYL-ALPHA-D-MALTOSIDE, ... (5 entities in total)
• 機能のキーワード: nuclear receptor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: P13631
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29192.51

構造登録者

Rochel, N.,Sirigu, S. (登録日: 2016-10-11, 公開日: 2017-09-20, 最終更新日: 2024-01-17)

主引用文献

Chebaro, Y.,Sirigu, S.,Amal, I.,Lutzing, R.,Stote, R.H.,Rochette-Egly, C.,Rochel, N.,Dejaegere, A.
Allosteric Regulation in the Ligand Binding Domain of Retinoic Acid Receptor gamma.
PLoS ONE, 12:e0171043-e0171043, 2017

PubMed Abstract: Retinoic acid (RA) plays key roles in cell differentiation and growth arrest through nuclear retinoic acid receptors (RARs), which are ligand-dependent transcription factors. While the main trigger of RAR activation is the binding of RA, phosphorylation of the receptors has also emerged as an important regulatory signal. Phosphorylation of the RARγ N-terminal domain (NTD) is known to play a functional role in neuronal differentiation. In this work, we investigated the phosphorylation of RARγ ligand binding domain (LBD), and present evidence that the phosphorylation status of the LBD affects the phosphorylation of the NTD region. We solved the X-ray structure of a phospho-mimetic mutant of the LBD (RARγ S371E), which we used in molecular dynamics simulations to characterize the consequences of the S371E mutation on the RARγ structural dynamics. Combined with simulations of the wild-type LBD, we show that the conformational equilibria of LBD salt bridges (notably R387-D340) are affected by the S371E mutation, which likely affects the recruitment of the kinase complex that phosphorylates the NTD. The molecular dynamics simulations also showed that a conservative mutation in this salt bridge (R387K) affects the dynamics of the LBD without inducing large conformational changes. Finally, cellular assays showed that the phosphorylation of the NTD of RARγ is differentially regulated by retinoic acid in RARγWT and in the S371N, S371E and R387K mutants. This multidisciplinary work highlights an allosteric coupling between phosphorylations of the LBD and the NTD of RARγ and supports the importance of structural dynamics involving electrostatic interactions in the regulation of RARs activity.

PubMed: 28125680
DOI: 10.1371/journal.pone.0171043

実験手法

X-RAY DIFFRACTION (1.69 Å)