Comprehensive set of tertiary complex structures and palmitic acid binding provide molecular insights into ligand design for RXR isoforms

  • 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.
Author:Apirat ChaikuadORCiD, Julius Pollinger, Michael Rühl, Xiaomin NiORCiDGND, Whitney KiluGND, Jan Peter HeeringORCiDGND, Daniel MerkORCiDGND
Parent Title (English):International Journal of Molecular Sciences
Place of publication:Basel
Document Type:Article
Date of Publication (online):0202/11/11
Date of first Publication:2020/11/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/04/13
Tag:neurodegeneration; nuclear receptor; retinoid X receptor; stearic acid
Issue:art. 8457
Page Number:13
First Page:1
Last Page:13
© 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 (
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0