دورية أكاديمية
Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.
| العنوان: | Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu. |
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| المؤلفون: | Min, Charles K, Nwachukwu, Jerome C, Hou, Yingwei, Russo, Robin J, Papa, Alexandra, Min, Jian, Peng, Rouming, Kim, Sung Hoon, Ziegler, Yvonne, Rangarajan, Erumbi S, Izard, Tina, Katzenellenbogen, Benita S, Katzenellenbogen, John A, Nettles, Kendall W |
| المصدر: | Proc Natl Acad Sci U S A ; ISSN:1091-6490 ; Volume:121 ; Issue:24 |
| بيانات النشر: | Atypon |
| سنة النشر: | 2024 |
| المجموعة: | PubMed Central (PMC) |
| مصطلحات موضوعية: | X-ray crystallography, estrogen receptor, molecular dynamics simulations |
| الوصف: | The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.1073/pnas.2321344121Test; https://pubmed.ncbi.nlm.nih.gov/38830107Test |
| DOI: | 10.1073/pnas.2321344121 |
| الإتاحة: | https://doi.org/10.1073/pnas.2321344121Test https://pubmed.ncbi.nlm.nih.gov/38830107Test |
| رقم الانضمام: | edsbas.C82423A9 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1073/pnas.2321344121 |
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