4Q13

Apo Estrogen Receptor Alpha Ligand Binding Domain D538G Mutant with a glucocorticoid receptor-interacting protein 1 NR box II peptide

Summary for 4Q13

• Entry DOI: 10.2210/pdb4q13/pdb
• Related: 4PXM 4PY1
• Descriptor: Estrogen receptor, Glucocorticoid receptor-interacting protein 1 NR box II peptide (3 entities in total)
• Functional Keywords: metastatic breast cancer, activating point mutation, drug resistance, serm resistance, alpha helix, nuclear hormone receptor, hormone binding protein-peptide complex, hormone binding protein/peptide
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 62631.76

Authors

Fanning, S.W.,Panchamukhi, S.,Greene, G.L. (deposition date: 2014-04-02, release date: 2015-04-08, Last modification date: 2024-02-28)

Primary citation

Fanning, S.W.,Mayne, C.G.,Dharmarajan, V.,Carlson, K.E.,Martin, T.A.,Novick, S.J.,Toy, W.,Green, B.,Panchamukhi, S.,Katzenellenbogen, B.S.,Tajkhorshid, E.,Griffin, P.R.,Shen, Y.,Chandarlapaty, S.,Katzenellenbogen, J.A.,Greene, G.L.
Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.
Elife, 5:-, 2016

PubMed Abstract: Somatic mutations in the estrogen receptor alpha (ERα) gene (ESR1), especially Y537S and D538G, have been linked to acquired resistance to endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity and antiestrogen resistance and suggest that ligand-binding domain dysfunction leads to endocrine therapy resistance. Here, we integrate biophysical and structural biology data to reveal how these mutations lead to a constitutively active and antiestrogen-resistant ERα. We show that these mutant ERs recruit coactivator in the absence of hormone while their affinities for estrogen agonist (estradiol) and antagonist (4-hydroxytamoxifen) are reduced. Further, they confer antiestrogen resistance by altering the conformational dynamics of the loop connecting Helix 11 and Helix 12 in the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state that resists inhibition.

PubMed: 26836308
DOI: 10.7554/eLife.12792

Experimental method

X-RAY DIFFRACTION (2.24 Å)