5DVV: Crystal Structure Of The Er-alpha Ligand-binding Domain In Complex With A Triaryl-imine Analog 4,4'-(phenylcarbonimidoyl)diphenol

Some estrogen receptor-alpha (ERalpha)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERalpha ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERalpha activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERalpha.
PDB ID: 5DVVDownload
MMDB ID: 138865
PDB Deposition Date: 2015/9/21
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2.51  Å
Source Organism:
Similar Structures:
Biological Unit for 5DVV: tetrameric; determined by author and by software (PISA)
Molecular Components in 5DVV
Label Count Molecule
Proteins (4 molecules)
Estrogen Receptor(Gene symbol: ESR1)
Molecule annotation
Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB