A ternary switch model governing ERα ligand binding domain conformation

Daniel P. McDougal, Jordan L. Pederick, Scott J. Novick, Blagojce Jovcevski, Annmaree K. Warrender, Bruce D. Pascal, Patrick R. Griffin and John B. Bruning ()
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Daniel P. McDougal: The University of Adelaide, Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences
Jordan L. Pederick: The University of Adelaide, Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences
Scott J. Novick: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Department of Molecular Medicine
Blagojce Jovcevski: The University of Adelaide, Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences
Annmaree K. Warrender: Australian Nuclear Science & Technology Organisation, Australian Synchrotron
Bruce D. Pascal: Omics Informatics LLC.
Patrick R. Griffin: The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Department of Molecular Medicine
John B. Bruning: The University of Adelaide, Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract The transcription factor estrogen receptor α is the primary driver of ER+ breast cancer progression and a target of multiple FDA-approved anticancer drugs. Ligand-dependent activity of ERα 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 α 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 α and have significant implications for therapeutic intervention.

Date: 2025
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DOI: 10.1038/s41467-025-65323-9

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