TY  - JOUR
A1  - Chaikuad, Apirat
A1  - Pollinger, Julius
A1  - Rühl, Michael
A1  - Ni, Xiaomin
A1  - Kilu, Whitney
A1  - Heering, Jan Peter
A1  - Merk, Daniel
T1  - Comprehensive set of tertiary complex structures and palmitic acid binding provide molecular insights into ligand design for RXR isoforms
T2  - International Journal of Molecular Sciences
N2  - The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.
KW  - nuclear receptor
KW  - retinoid X receptor
KW  - stearic acid
KW  - neurodegeneration
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/57682
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-576822
SN  - 1422-0067
N1  - © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
VL  - 21
IS  - art. 8457
SP  - 1
EP  - 13
PB  - MDPI
CY  - Basel
ER  -