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Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.
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.
Afiliación
  • Min CK; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
  • Nwachukwu JC; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037.
  • Hou Y; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
  • Russo RJ; Department of Chemistry and Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
  • Papa A; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
  • Min J; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037.
  • Peng R; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
  • Kim SH; Florida Atlantic University, Jupiter, FL 33458.
  • Ziegler Y; State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, China.
  • Rangarajan ES; State Key Laboratory of Biocatalysis and Enzyme Engineering, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan 430062, China.
  • Izard T; Department of Chemistry and Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL 61801.
  • Katzenellenbogen BS; Department of Molecular and Integrative Physiology, Cancer Center at University of Illinois at Urbana-Champaign, Urbana, IL 61801.
  • Katzenellenbogen JA; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
  • Nettles KW; Department of Immunology and Microbiology, The Herbert Wertheim University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458.
Proc Natl Acad Sci U S A ; 121(24): e2321344121, 2024 Jun 11.
Article en En | MEDLINE | ID: mdl-38830107
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptor alfa de Estrógeno / Estrógenos / Multimerización de Proteína / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Receptor alfa de Estrógeno / Estrógenos / Multimerización de Proteína / Simulación de Dinámica Molecular Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article