Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization

Research output: Contribution to journalArticle

Abstract

Retinoid X receptors (RXRs) play key roles in many physiological processes in both the periphery and central nervous system. In addition, RXRs form heterodimers with other nuclear receptors to exert their physiological effects. The nuclear receptor related 1 protein (NURR1) is particularly interesting because of its role in promoting differentiation and survival of dopamine neurons. However, only a small number of RXR-heterodimer selective modulators are available, with limited chemical diversity. This work describes the synthesis, biochemical evaluation, and structural elucidation of a novel series of RXR ligands with strongly biased interactions with RXRα-NURR1 heterodimers. Targeted modifications to the small molecule biaryl scaffold caused local RXRα side-chain disturbances and displacement of secondary structural elements upon ligand binding. This resulted in the repositioning of protein helices in the heterodimer interface of RXRα, alterations in homo- versus heterodimer formation, and modulation of activation function 2 (AF2). The data provide a rationale for the design of RXR ligands consisting of a highly conserved hydrophilic region, strongly contributing to the ligand affinity, and a variable hydrophobic region, which efficiently probes the effects of structural changes at the level of the ligand on co-regulator recruitment or the RXRα-NURR1 dimerization interface.

Details

Authors
  • Marcel Scheepstra
  • Sebastian A. Andrei
  • Rens M.J.M. De Vries
  • Femke A. Meijer
  • Jian-Nong Ma
  • Ethan S Burstein
  • Roger Olsson
  • Christian Ottmann
  • Lech Gustav Milroy
  • Luc Brunsveld
Organisations
External organisations
  • Eindhoven University of Technology
  • ACADIA Pharmaceuticals Inc.
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medicinal Chemistry

Keywords

  • heterodimerization, ligand binding domain, nuclear receptor related 1, Nuclear receptors, retinoid X receptor
Original languageEnglish
Pages (from-to)2065-2077
Number of pages13
JournalACS Chemical Neuroscience
Volume8
Issue number9
Publication statusPublished - 2017 Sep 20
Publication categoryResearch
Peer-reviewedYes