A ternary switch model governing ERα ligand binding domain conformation.

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 evolutionari

SUBMITTER: McDougal DP 

PROVIDER: S-EPMC12644489 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature