7B9O
Crystal structure of Retinoic Acid Receptor alpha (RXRA) in complexed with S169 inhibitor
Summary for 7B9O
| Entry DOI | 10.2210/pdb7b9o/pdb |
| Descriptor | Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, 3-(5-(3,5-bis(trifluoromethyl)phenyl)-4-phenyloxazol-2-yl)propanoic acid, ... (4 entities in total) |
| Functional Keywords | complex, structural genomics, structural genomics consortium, sgc, dna binding protein |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 27990.34 |
| Authors | Ni, X.,Chaikuad, A.,Schierle, S.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-12-14, release date: 2021-02-10, Last modification date: 2024-01-31) |
| Primary citation | Schierle, S.,Chaikuad, A.,Lillich, F.F.,Ni, X.,Woltersdorf, S.,Schallmayer, E.,Renelt, B.,Ronchetti, R.,Knapp, S.,Proschak, E.,Merk, D. Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics. J.Med.Chem., 64:5123-5136, 2021 Cited by PubMed Abstract: The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR. PubMed: 33793232DOI: 10.1021/acs.jmedchem.1c00235 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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