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

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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; Ottmann, Christian; Milroy, Lech Gustav; Brunsveld, Luc.

I: ACS Chemical Neuroscience, Vol. 8, Nr. 9, 20.09.2017, s. 2065-2077.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Scheepstra, M, Andrei, SA, De Vries, RMJM, Meijer, FA, Ma, J-N, Burstein, ES, Olsson, R, Ottmann, C, Milroy, LG & Brunsveld, L 2017, 'Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization', ACS Chemical Neuroscience, vol. 8, nr. 9, s. 2065-2077. https://doi.org/10.1021/acschemneuro.7b00216

APA

Scheepstra, M., Andrei, S. A., De Vries, R. M. J. M., Meijer, F. A., Ma, J-N., Burstein, E. S., ... Brunsveld, L. (2017). Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chemical Neuroscience, 8(9), 2065-2077. https://doi.org/10.1021/acschemneuro.7b00216

CBE

Scheepstra M, Andrei SA, De Vries RMJM, Meijer FA, Ma J-N, Burstein ES, Olsson R, Ottmann C, Milroy LG, Brunsveld L. 2017. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chemical Neuroscience. 8(9):2065-2077. https://doi.org/10.1021/acschemneuro.7b00216

MLA

Vancouver

Scheepstra M, Andrei SA, De Vries RMJM, Meijer FA, Ma J-N, Burstein ES et al. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chemical Neuroscience. 2017 sep 20;8(9):2065-2077. https://doi.org/10.1021/acschemneuro.7b00216

Author

Scheepstra, Marcel ; Andrei, Sebastian A. ; De Vries, Rens M.J.M. ; Meijer, Femke A. ; Ma, Jian-Nong ; Burstein, Ethan S ; Olsson, Roger ; Ottmann, Christian ; Milroy, Lech Gustav ; Brunsveld, Luc. / Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. I: ACS Chemical Neuroscience. 2017 ; Vol. 8, Nr. 9. s. 2065-2077.

RIS

TY - JOUR

T1 - Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization

AU - Scheepstra, Marcel

AU - Andrei, Sebastian A.

AU - De Vries, Rens M.J.M.

AU - Meijer, Femke A.

AU - Ma, Jian-Nong

AU - Burstein, Ethan S

AU - Olsson, Roger

AU - Ottmann, Christian

AU - Milroy, Lech Gustav

AU - Brunsveld, Luc

PY - 2017/9/20

Y1 - 2017/9/20

N2 - 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.

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 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.

KW - heterodimerization

KW - ligand binding domain

KW - nuclear receptor related 1

KW - Nuclear receptors

KW - retinoid X receptor

U2 - 10.1021/acschemneuro.7b00216

DO - 10.1021/acschemneuro.7b00216

M3 - Article

VL - 8

SP - 2065

EP - 2077

JO - ACS Chemical Neuroscience

T2 - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 9

ER -