9MDV

Apo form of the estrogen receptor alpha ligand binding domain of Melanotaenia fluviatilis

Summary for 9MDV

• Entry DOI: 10.2210/pdb9mdv/pdb
• Descriptor: Estrogen receptor, GLYCEROL (3 entities in total)
• Functional Keywords: transcription factor, ligand binding, endocrine signalling, nuclear protein
• Biological source: Melanotaenia fluviatilis (Murray River rainbowfish)
• Total number of polymer chains: 2
• Total formula weight: 57798.12

Authors

Pederick, J.L.,McDougal, D.P.,Bruning, J.B. (deposition date: 2024-12-05, release date: 2025-10-22, Last modification date: 2025-12-24)

Primary citation

McDougal, D.P.,Pederick, J.L.,Novick, S.J.,Jovcevski, B.,Warrender, A.K.,Pascal, B.D.,Griffin, P.R.,Bruning, J.B.
A ternary switch model governing ER alpha ligand binding domain conformation.
Nat Commun, 16:10363-10363, 2025

PubMed 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.

PubMed: 41285747
DOI: 10.1038/s41467-025-65323-9

Experimental method

X-RAY DIFFRACTION (2 Å)