Fig. 1

Structural basis of T6I-29 efficacy in Y537S ESR1 breast cancer cells. A) Overview of the Y537S ERα LBD homodimer x-ray co-crystal structure with T6I-29 (green sticks) bound in the hormone binding pocket. Helix 12 (H12) is highlighted in green. B) T6I-29 interactions with residues in the hormone binding pocket, the difference density map of relevant atoms are shown in blue mesh. C) Difference density map from the Y537S-4OHT x-ray co-crystal structure highlighting the poor density of H12 that is representative of poor transcriptional antagonists in Y537S ESR1 breast cancer cells. D) Difference density map from the Y537S-RAL x-ray co-crystal structure highlighting the improved density of H12 that is found in effective transcriptional antagonists in Y537S ESR1 breast cancer cells. E) Superposition of T6I-29 (green) with RAL (blue) x-ray co-crystal structures. F) Superposition of T6I-29 in complex with WT (cyan) or Y537S (green) ERα LBD. G) Chemical structures of T6I-29, T6I-14-1, and T6I-4-1. H) Side-by-side comparison of ligand, E380, and S537 difference density maps for T6I-29, T6I-14-1, or T6I-4-1 in complex with Y537S ERα LBD. All difference density maps are 2mFo-DFc and are contoured to 1.0 σ. Protein DataBank (PDB) accession codes are: 9BPX for Y537S-T6I-29, 7UJ8 for Y537S-4OHT, 7UJC for Y537S-RAL, 8DVB for WT-T6I-29, 9BQE for Y537S-T6I-14-1, and 9BU1 for Y537S-T6I-4-1