Summary for 6C42
| Entry DOI | 10.2210/pdb6c42/pdb |
| Descriptor | Estrogen receptor, (2R,3S,4R)-3-(4-hydroxyphenyl)-4-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3,4-dihydro-2H-1-benzopyran-7-ol (3 entities in total) |
| Functional Keywords | estrogen receptor alpha, antiestrogen, selective estrogen receptor degrader, endocrine therapy, steroid receptor, nuclear hormone receptor, breast cancer, acquired antiestrogen resistance, transcription, trascription-transcription inhibitor complex, trascription/transcription inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 57601.51 |
| Authors | Fanning, S.W.,Hodges-Gallager, L.,Myles, D.C.,Sun, R.,Fowler, C.E.,Green, B.D.,Harmon, C.L.,Greene, G.L.,Kushner, P.J. (deposition date: 2018-01-11, release date: 2018-02-14, Last modification date: 2023-10-04) |
| Primary citation | Fanning, S.W.,Hodges-Gallagher, L.,Myles, D.C.,Sun, R.,Fowler, C.E.,Plant, I.N.,Green, B.D.,Harmon, C.L.,Greene, G.L.,Kushner, P.J. Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity. Nat Commun, 9:2368-2368, 2018 Cited by PubMed Abstract: Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12. PubMed: 29915250DOI: 10.1038/s41467-018-04413-3 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.997 Å) |
Structure validation
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