5U2D

Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in complex with Oxabicyclic Heptene Sulfonate (OBHS)

Summary for 5U2D

• Entry DOI: 10.2210/pdb5u2d/pdb
• Related: 5U2B
• Descriptor: Estrogen receptor, Nuclear receptor coactivator 2, cyclohexa-2,5-dien-1-yl (1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonate, ... (4 entities in total)
• Functional Keywords: protein ligand complex, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372; Nucleus: Q15596
• Total number of polymer chains: 4
• Total formula weight: 62635.79

Authors

Nwachukwu, J.C.,Erumbi, R.,Nowak, J.,Carlson, K.E.,Katzenellenbogen, J.A.,Izard, T.,Nettles, K.W. (deposition date: 2016-11-30, release date: 2017-04-05, Last modification date: 2024-03-06)

Primary citation

Stender, J.D.,Nwachukwu, J.C.,Kastrati, I.,Kim, Y.,Strid, T.,Yakir, M.,Srinivasan, S.,Nowak, J.,Izard, T.,Rangarajan, E.S.,Carlson, K.E.,Katzenellenbogen, J.A.,Yao, X.Q.,Grant, B.J.,Leong, H.S.,Lin, C.Y.,Frasor, J.,Nettles, K.W.,Glass, C.K.
Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells.
Mol. Cell, 65:1122-1135.e5, 2017

PubMed Abstract: Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKβ signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.

PubMed: 28306507
DOI: 10.1016/j.molcel.2017.02.008

Experimental method

X-RAY DIFFRACTION (1.86 Å)