5MJ5

Crystal structure of the Retinoid X Receptor alpha in complex with synthetichonokiol derivative 3 and a fragment of the TIF2 co-activator.

Summary for 5MJ5

• Entry DOI: 10.2210/pdb5mj5/pdb
• Descriptor: Retinoic acid receptor RXR-alpha, LYS-HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP-SER, (~{E})-3-[4-oxidanyl-3-[3-(phenylmethyl)phenyl]phenyl]prop-2-enoic acid, ... (4 entities in total)
• Functional Keywords: rxr tif2 honokiol, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : P19793
• Total number of polymer chains: 2
• Total formula weight: 27581.04

Authors

Andrei, S.A.,Brunsveld, L.,Scheepstra, M.,Ottmann, C. (deposition date: 2016-11-30, release date: 2017-11-08, Last modification date: 2024-01-17)

Primary citation

Scheepstra, M.,Andrei, S.A.,de Vries, R.M.J.M.,Meijer, F.A.,Ma, J.N.,Burstein, E.S.,Olsson, R.,Ottmann, C.,Milroy, L.G.,Brunsveld, L.
Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization.
ACS Chem Neurosci, 8:2065-2077, 2017

PubMed 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.

PubMed: 28691794
DOI: 10.1021/acschemneuro.7b00216

Experimental method

X-RAY DIFFRACTION (1.9 Å)