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

Scheepstra, Marcel; Andrei, Sebastian A.; De Vries, Rens M.J.M.; Meijer, Femke A.; Ma, Jian-Nong; Burstein, Ethan S; Olsson, Roger LU ; Ottmann, Christian; Milroy, Lech Gustav and Brunsveld, Luc (2017) In ACS Chemical Neuroscience 8(9). p.2065-2077
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... (More)

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.

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Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
heterodimerization, ligand binding domain, nuclear receptor related 1, Nuclear receptors, retinoid X receptor
in
ACS Chemical Neuroscience
volume
8
issue
9
pages
13 pages
publisher
The American Chemical Society
external identifiers
  • scopus:85029657893
  • wos:000411662000029
ISSN
1948-7193
DOI
10.1021/acschemneuro.7b00216
language
English
LU publication?
yes
id
6ad6f346-6bbf-4a8b-ad66-3931b86ca55c
date added to LUP
2017-09-29 09:26:37
date last changed
2018-01-16 13:19:57
@article{6ad6f346-6bbf-4a8b-ad66-3931b86ca55c,
  abstract     = {<p>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.</p>},
  author       = {Scheepstra, Marcel and Andrei, Sebastian A. and De Vries, Rens M.J.M. and Meijer, Femke A. and Ma, Jian-Nong and Burstein, Ethan S and Olsson, Roger and Ottmann, Christian and Milroy, Lech Gustav and Brunsveld, Luc},
  issn         = {1948-7193},
  keyword      = {heterodimerization,ligand binding domain,nuclear receptor related 1,Nuclear receptors,retinoid X receptor},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {2065--2077},
  publisher    = {The American Chemical Society},
  series       = {ACS Chemical Neuroscience},
  title        = {Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization},
  url          = {http://dx.doi.org/10.1021/acschemneuro.7b00216},
  volume       = {8},
  year         = {2017},
}