A ternary switch model governing ERĪ± ligand binding domain conformation
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Date
2025
Authors
McDougal, D.P.
Pederick, J.L.
Novick, S.J.
Jovcevski, B.
Warrender, A.K.
Pascal, B.D.
Griffin, P.R.
Bruning, J.B.
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Journal article
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Nature Communications, 2025; 16(1):10363-1-10363-13
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Daniel P. McDougal, Jordan L. Pederick, Scott J. Novick, Blagojce Jovcevski, Annmaree K. Warrender, Bruce D. Pascal, Patrick R. Griffin, John B. Bruning
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Abstract
The transcription factor estrogen receptor Ī± is the primary driver of ER+ breast cancer progression and a target of multiple FDA-approved anticancer drugs. Ligand-dependent activity of ERĪ± is determined by helix-12 conformation within the ligand binding domain. However, how helix-12 transitions from an unliganded (apo) state to active (estrogen-bound) or inactive (SERM/SERD-bound) states remains unresolved. Here, we present the crystal structure of an apo estrogen receptor Ī± ligand binding domain from the teleost Melanotaenia fluviatilis, revealing a third distinct helix-12 conformation. Structural mass spectrometry and molecular dynamics simulations reveal that apo helix-12 is maintained in a stable and distinct conformation prior to ligand binding. Clashes between ligand and evolutionarily conserved residues L525, L536 and L540 displace helix-12, to promote activation or inactivation of the receptor. The crystal structure further reveals that breast cancer-associated mutations, Y537S and D538G, disrupt residue contacts critical for stabilising apo helix-12 conformation. We propose a model whereby helix-12 functions as a ternary molecular switch to determine receptor activity. These findings provide critical insights into the ligand-dependent and -independent regulation of estrogen receptor Ī± and have significant implications for therapeutic intervention.
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Published online: 24 November 2025
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Ā© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived fromthis article or parts of it. The images or other third party material in this article are included in the articleās Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the articleās Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.