PMID- 28691794
OWN - NLM
STAT- MEDLINE
DCOM- 20180612
LR  - 20201209
IS  - 1948-7193 (Electronic)
IS  - 1948-7193 (Linking)
VI  - 8
IP  - 9
DP  - 2017 Sep 20
TI  - Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization.
PG  - 2065-2077
LID - 10.1021/acschemneuro.7b00216 [doi]
AB  - 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 RXRalpha-NURR1 heterodimers. Targeted 
      modifications to the small molecule biaryl scaffold caused local RXRalpha 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 RXRalpha, 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 RXRalpha-NURR1 dimerization interface.
FAU - Scheepstra, Marcel
AU  - Scheepstra M
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - Andrei, Sebastian A
AU  - Andrei SA
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - de Vries, Rens M J M
AU  - de Vries RMJM
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - Meijer, Femke A
AU  - Meijer FA
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - Ma, Jian-Nong
AU  - Ma JN
AD  - ACADIA Pharmaceuticals Inc., San Diego, California 92130, United States.
FAU - Burstein, Ethan S
AU  - Burstein ES
AD  - ACADIA Pharmaceuticals Inc., San Diego, California 92130, United States.
FAU - Olsson, Roger
AU  - Olsson R
AD  - Chemical Biology & Therapeutics, Department of Experimental Medical Science, Lund 
      University , SE-221 00 Lund, Sweden.
FAU - Ottmann, Christian
AU  - Ottmann C
AUID- ORCID: 0000-0001-7315-0315
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - Milroy, Lech-Gustav
AU  - Milroy LG
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
FAU - Brunsveld, Luc
AU  - Brunsveld L
AUID- ORCID: 0000-0001-5675-511X
AD  - Department of Biomedical Engineering and Institute for Complex Molecular Systems, 
      Laboratory of Chemical Biology, Technische Universiteit Eindhoven , Den Dolech 2, 
      5612 AZ Eindhoven, The Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20170724
PL  - United States
TA  - ACS Chem Neurosci
JT  - ACS chemical neuroscience
JID - 101525337
RN  - 0 (Esters)
RN  - 0 (Ethers)
RN  - 0 (Ligands)
RN  - 0 (Nuclear Receptor Subfamily 4, Group A, Member 2)
RN  - 0 (Retinoid X Receptor alpha)
SB  - IM
MH  - Drug Design
MH  - Escherichia coli
MH  - Esters/chemistry
MH  - Ethers/chemistry
MH  - Humans
MH  - Hydrogen Bonding
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Nuclear Receptor Subfamily 4, Group A, Member 2/agonists/antagonists & 
      inhibitors/*chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Multimerization
MH  - Retinoid X Receptor alpha/agonists/antagonists & 
      inhibitors/*chemistry/*metabolism
MH  - Two-Hybrid System Techniques
PMC - PMC5609127
OTO - NOTNLM
OT  - Nuclear receptors
OT  - heterodimerization
OT  - ligand binding domain
OT  - nuclear receptor related 1
OT  - retinoid X receptor
COIS- The authors declare no competing financial interest.
EDAT- 2017/07/12 06:00
MHDA- 2018/06/13 06:00
PMCR- 2017/09/22
CRDT- 2017/07/11 06:00
PHST- 2017/07/12 06:00 [pubmed]
PHST- 2018/06/13 06:00 [medline]
PHST- 2017/07/11 06:00 [entrez]
PHST- 2017/09/22 00:00 [pmc-release]
AID - 10.1021/acschemneuro.7b00216 [doi]
PST - ppublish
SO  - ACS Chem Neurosci. 2017 Sep 20;8(9):2065-2077. doi: 10.1021/acschemneuro.7b00216. 
      Epub 2017 Jul 24.