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Estrogen receptor

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Revision as of 11:45, 2 October 2014

Human estrogen receptor-ligand binding domain (grey and green) complex with transcription intermediate factor-2 peptide (pink and yellow) and estradiol (PDB code 1gwr)

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Crystal structure of estradiol derived metal chelate and estrogen receptor-ligand binding domain complex 2yat

Estrogen receptors (ER) are activated by the hormone estrogen (EST). The activated ER binds DNA and regulates the activity of many genes. There are 2 forms of ER: α and β and ER dimers can be of αα, ββ and αβ. ER is composed of 5 domains: N terminal A/B domain can transactivate transcription without binding estrogen; C domain (DBD) binds to Estrogen response elements of DNA; D domain is a hinge region; E domain is ligand binding (LBD) as well as binding the coactivator and corepressor proteins and transactivates gene transcription.

Structure of estradiol metal chelate and estrogen receptor complex: The basis for designing a new class of SERMs ^[1]

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.

Estrogen receptor α complexed with raloxifene and a corepressor peptide
of estrogen receptor α complexed with raloxifene and a corepressor peptide (morph was taken from Gallery of Morphs of the Yale Morph Server).

3D structures of estrogen receptor

Updated on 02-October-2014

Estrogen receptor α ligand binding domain

3ltx, 4n1y - ERα LBD – pacific oyster
1a52, 1g50 - hERα LBD - human
1ere, 1qku - hERα LBD + EST
1qkt - hERα LBD (mutant) + EST
1uom, 2ayr, 2q70, 2qe4, 2pog, 2r6w, 2r6y, 2qxs - hERα LBD (mutant) + ligand
1err, 3ert, 1sj0, 1yim, 1r5k, 1xp1, 1xp6, 1xp9, 1xpc, 1xqc, 1yin, 2ouz, 2iog, 2iok, 3dt3, 3os8, 3os9, 3osa - hERα LBD + ligand
2bj4, 2jf9, 2jfa, 1pcg - hERα LBD + peptide antagonist
2yja - hERα LBD + stapled peptide
2yat - hERα LBD (mutant) + EST derivative
3uuc - hERα LBD + bisphenol

ERα LBD ternary complex with steroid receptor coactivator peptide

2b23, 3uu7, 3uua, 3uud - hERα LBD (mutant) + nuclear receptor coactivator peptide
3erd, 1l2i - hERα LBD + nuclear receptor coactivator peptide + nonsteroidal EST
1gwr - hERα LBD + nuclear receptor coactivator peptide + EST
3q95 - hERα LBD (mutant) + nuclear receptor coactivator peptide + EST
4dma, 4iu7, 4iui, 4iv2, 4iv4, 4ivw, 4ivy, 4iw6, 4iw8, 4iwc, 4iwf - hERα LBD (mutant) + nuclear receptor coactivator peptide + inhibitor
2g5o - hERα LBD + nuclear receptor coactivator peptide + EST derivative
2p15, 2qgt - hERα LBD (mutant) + nuclear receptor coactivator peptide + EST derivative
1gwq, 1x7e, 2fai, 2g44, 2q6j, 2qzo - hERα LBD + nuclear receptor coactivator peptide + ligand
1zky, 2b1v, 2b1z, 2qa6, 2qab, 2qgw, 2qh6, 2qr9, 2qse, 2qxm, 3hlv, 3hm1, 3l03, 3q97, 3dma - hERα LBD (mutant) + nuclear receptor coactivator peptide + ligand
1x7r - hERα LBD + steroid receptor coactivator peptide + genistein
2qa8 - hERα LBD (mutant) + steroid receptor coactivator peptide + genistein
2ocf - hERα LBD (mutant) + fibronectin domain 10 + EST

Estrogen receptor β ligand binding domain

1qkm - hERβ LBD + genistein
1qkn, 1hj1 - ERβ LBD + ligand – rat
1nde, 1u3q, 1u3r, 1u3s, 2giu, 2i0g, 2i0j, 2jj3, 2z4b, 2qtu - hERβ LBD + ligand
2yly - hERβ LBD + sulfonamide agonist
2fsz - hERβ LBD (mutant) + ligand
2yja - hERβ LBD + stapled peptide
4j24, 4j26 - hERβ LBD + peptide

ERβ LBD ternary complex with steroid receptor coactivator peptide

1l2j - hERβ LBD + steroid receptor coactivator peptide + nonsteroidal EST
2j7x, 3oll, 3ols - hERβ LBD + steroid receptor coactivator peptide + EST
1u9e - hERβ LBD + steroid receptor coactivator peptide
1x76, 1x78, 1x7b, 1yy4, 1yye, 1zaf, 2j7y, 2nv7, 3omo, 3omp, 3omq - hERβ LBD + steroid receptor coactivator peptide + ligand
1x7j - hERβ LBD + steroid receptor coactivator peptide + genistein

Estrogen receptor α DNA binding domain

1hcp – hERα DBD – NMR
1hcq, 4aa6 – hERα DBD + DNA

Reference

↑ Li MJ, Greenblatt HM, Dym O, Albeck S, Pais A, Gunanathan C, Milstein D, Degani H, Sussman JL. Structure of estradiol metal chelate and estrogen receptor complex: The basis for designing a new class of selective estrogen receptor modulators. J Med Chem. 2011 Apr 7. PMID:21473635 doi:10.1021/jm200192y