7CFO
Crystal structure of human RXRalpha ligand binding domain complexed with CBTF-EE.
Summary for 7CFO
| Entry DOI | 10.2210/pdb7cfo/pdb |
| Descriptor | Retinoic acid receptor RXR-alpha, 1-[3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl]-2-(trifluoromethyl)benzimidazole-5-carboxylic acid, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | retinoid x receptor alpha, antagonist, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 110194.98 |
| Authors | Watanabe, M.,Fujihara, M.,Motoyama, T.,Kawasaki, M.,Yamada, S.,Takamura, Y.,Ito, S.,Makishima, M.,Nakano, S.,Kakuta, H. (deposition date: 2020-06-27, release date: 2021-01-06, Last modification date: 2024-11-06) |
| Primary citation | Watanabe, M.,Fujihara, M.,Motoyama, T.,Kawasaki, M.,Yamada, S.,Takamura, Y.,Ito, S.,Makishima, M.,Nakano, S.,Kakuta, H. Discovery of a "Gatekeeper" Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers. J.Med.Chem., 64:430-439, 2021 Cited by PubMed Abstract: Retinoid X receptor (RXR) heterodimers such as PPAR/RXR, LXR/RXR, and FXR/RXR can be activated by RXR agonists alone and are therefore designated as permissive. Similarly, existing RXR antagonists show allosteric antagonism toward partner receptor agonists in these permissive RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1-benzo[]imidazole-5-carboxylic acid (, CBTF-EE) as the first RXR antagonist that does not show allosteric inhibition in permissive RXR heterodimers. This compound was designed based on the hypothesis that RXR antagonists that do not induce conformational changes of RXR would not exhibit such allosteric inhibition. CD spectra and X-ray co-crystallography of the complex of and the RXR ligand binding domain (LBD) confirmed that does not change the conformation of hRXR-LBD. The X-ray structure analysis revealed that binds at the entrance of the ligand binding pocket (LBP), blocking access to the LBP and thus serving as a "gatekeeper". PubMed: 33356247DOI: 10.1021/acs.jmedchem.0c01354 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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