Journal:JMedChem:1

Structure of estradiol metal chelate and estrogen receptor complex: The basis for designing a new class of SERMs

Min-Jun Li, Harry M. Greenblatt, Orly Dym, Shira Albeck, Adi Pais, Chidambaram Gunanathan, David Milstein, Hadassa Degani, and Joel L. Sussman ^[1]

Molecular Tour

Selective estrogen receptor 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 bound with a novel at 2.6 resolution. The residues with EPTA-Eu. The hydrogen bonds are shown as white dashed lines. of this structure with the structure of native ligand 17β-estradiol (E2) in the complex of E2/ERα-LBD complex (1ere) reveals that the . The made by additional estrogen receptor residues (e.g. Glu419 of H7 and Glu339 of H3, this depends on subunit), may work together with the E2 17β hydroxyl-His524 hydrogen bond and tighten the neck of the LBP upon binding of the endogenous ligand E2. 4-Hydroxytamoxifen (OHT) is an other selective estrogen receptor modulator. of EPTA-Eu/ERα-LBD complex on OHT/ERα-LBD complex (3ert) shows that there is similar network of hydrogen bonds in both complexes, except for His524 which does not form hydrogen bond with OHT in the OHT/ERα-LBD complex. 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.

PDB reference: Crystal structure of estradiol derived metal chelate and estrogen receptor-ligand binding domain complex, 2yat.