8PP0
Crystal structure of Retinoic Acid Receptor alpha (RXRA) in complexed with JP147
Summary for 8PP0
| Entry DOI | 10.2210/pdb8pp0/pdb |
| Descriptor | Retinoic acid receptor RXR-alpha, Nuclear receptor coactivator 2, 3-[4-[2,3-dihydro-1H-inden-4-yl(methyl)amino]-6-(trifluoromethyl)pyrimidin-2-yl]oxypropanoic acid, ... (4 entities in total) |
| Functional Keywords | rxr alpha, inhibitor, structural genomics, structural genomics consortium, sgc, dna binding protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 29198.70 |
| Authors | Chaikuad, A.,Pollinger, J.,Merk, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-07-05, release date: 2024-02-07, Last modification date: 2024-02-21) |
| Primary citation | Lewandowski, M.,Carmina, M.,Knumann, L.,Sai, M.,Willems, S.,Kasch, T.,Pollinger, J.,Knapp, S.,Marschner, J.A.,Chaikuad, A.,Merk, D. Structure-Guided Design of a Highly Potent Partial RXR Agonist with Superior Physicochemical Properties. J.Med.Chem., 67:2152-2164, 2024 Cited by PubMed Abstract: Retinoid X receptors (RXRs, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9- retinoic acid exhibit poor physicochemical properties, pharmacokinetics, and safety profiles. Improved RXR ligands are needed to exploit RXR modulation as a promising therapeutic concept in various indications beyond its current role in second-line cancer treatment. Here, we report the co-crystal structure of RXR in complex with a novel pyrimidine-based ligand and the structure-informed optimization of this scaffold to highly potent and highly soluble RXR agonists. Focused structure-activity relationship elucidation and rigidization resulted in a substantially optimized partial RXR agonist with low nanomolar potency, no cytotoxic activity, and very favorable physicochemical properties highlighting this promising scaffold for the development of next-generation RXR targeting drugs. PubMed: 38237049DOI: 10.1021/acs.jmedchem.3c02095 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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