Journal:JMedChem:1

Selective <scene name='Journal:JMEDCHEM:1/Cv/3'>estrogen receptor</scene> modulators, such as estradiol 17-derived metal complexes, have been synthesized as targeted probes for the diagnosis and treatment of breast cancer. Here, we report the detailed 3D structure of estrogen receptor α ligand-binding domain (ER-LBD) bound with a novel <scene name='Journal:JMEDCHEM:1/Cv/5'>estradiol-derived metal complex, estradiol-pyridinium tetra acetate europium (III) (EPTA-Eu)</scene> at 2.6 resolution. The residues <scene name='Journal:JMEDCHEM:1/Cv/6'>Glu353, Arg394 and His524 and the conserved water molecule (W1006) form hydrogen bonds</scene> with estrogen receptor. <scene name='Journal:JMEDCHEM:1/Cv/7'>Superposition</scene> of this structure with the structure of native ligand 17β-estradiol (E2) in the complex of E2/ERα-LBD complex ([[1ere]]) reveals that the <scene name='Journal:JMEDCHEM:1/Cv/8'>E2 core of EPTA-Eu overlaps closely with that of E2 itself</scene>. The <scene name='Journal:JMEDCHEM:1/Cv/9'>hydrogen bonds</scene> made by the 17β hydroxyl of E2 with His524 and additional residues (''e.g.'' Glu419 of H7 and Glu339 of H3, this depends on subunit within asymmetric unit), may work together to tighten the neck of the LBP upon binding of the endogenous ligand E2. <scene name='Journal:JMEDCHEM:1/Al/3'>Superposition</scene> of EPTA-Eu/ERα-LBD complex on OHT/ERα-LBD complex ([[3ert]]). <scene name='Journal:JMEDCHEM:1/Al/4'>There are no hydrogen bonds formed between OHT</scene> and residues in H3, H7-H8 and H11 within the OHT/ERα-LBD complex. <scene name='Journal:JMEDCHEM:1/Al1/3'>Superposition of structures of all these three complexes:</scene> E2/ERα-LBD ([[1ere]]), OHT/ERα-LBD ([[3ert]]) and EPTA-Eu/ERα-LBD shows that they overlap well in the majority portions of the domain, but differ significantly in the region of the 'omega loop'. They display different synergistic reciprocating movements, depending on the specific nature of the ligand bound. The structure of estrogen receptor complexed with EPTA-Eu provides important information pertinent to the design of novel functional ER targeted probes for clinical applications.