3FUG

Crystal Structure of the Retinoid X Receptor Ligand Binding Domain Bound to the Synthetic Agonist 3-[4-Hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-phenyl]acrylic Acid

Summary for 3FUG

• Entry DOI: 10.2210/pdb3fug/pdb
• Related: 2p1t 2p1u 2p1v
• Descriptor: Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, (2E)-3-[4-hydroxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]prop-2-enoic acid, ... (4 entities in total)
• Functional Keywords: protein-ligand complex, hormone receptor, dna-binding, host-virus interaction, metal-binding, nucleus, polymorphism, receptor, transcription, transcription regulation, ubl conjugation, zinc, zinc-finger, activator, phosphoprotein, transcription-transcription regulator complex, transcription/transcription regulator
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P19793 Q15596
• Total number of polymer chains: 2
• Total formula weight: 28756.37

Authors

Bourguet, W. (deposition date: 2009-01-14, release date: 2009-05-12, Last modification date: 2023-09-06)

Primary citation

Perez Santin, E.,Germain, P.,Quillard, F.,Khanwalkar, H.,Rodriguez-Barrios, F.,Gronemeyer, H.,de Lera, A.R.,Bourguet, W.
Modulating retinoid X receptor with a series of (E)-3-[4-hydroxy-3-(3-alkoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl]acrylic acids and their 4-alkoxy isomers.
J.Med.Chem., 52:3150-3158, 2009

PubMed Abstract: Rexinoids are ligands for the retinoid X receptor (RXR) that have great promise for both the prevention and treatment of cancer and metabolic diseases. In this regard, synthetic, functional, and structural investigations into the structure-activity relationships of derivatives of the potent RXR agonist (E)-3-[3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-hydroxyphenyl]acrylic acid (CD3254, 9) have been conducted. We recently reported on the characterization of a series of C3'-substituted alkyl ether analogues of 9 (10a-f), which display activities ranging from partial agonists to pure antagonists. The importance of the position of the alkoxy side chain for ligand activity has been further explored with the synthesis of C4'-substituted analogues (11a-f). Here we describe the synthesis of compounds 11a-f, which appear functionally different from their isomeric counterparts, as judged from transactivation assays and fluorescence anisotropy experiments. We also report on the 2.0 A resolution structure of RXR in complex with the parent compound 9, which helps understanding of the impact of the alkyl side chain location on ligand activity.

PubMed: 19408900
DOI: 10.1021/jm900096q

Experimental method

X-RAY DIFFRACTION (2 Å)