scholarly journals The physiological role of estrogen receptor functional domains

2021 ◽  
Author(s):  
Yukitomo Arao ◽  
Kenneth S. Korach
Keyword(s):  
Estrogen Receptor ◽  
Genomic Sequence ◽  
Physiological Role ◽  
Binding Domain ◽  
Transactivation Domains ◽  
Estrogen Receptor Modulators ◽  
Domain Structures ◽  
Sequence Recognition ◽  
Helix 12 ◽  
Estrogenic Chemicals

Abstract Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and ligand-binding domain (LBD). Estrogenic chemicals work as ligands for activation or repression of ER-mediated transcriptional activity derived from two transactivation domains: AF-1 and AF-2. AF-2 is localized in the LBD, and helix 12 of the LBD is essential for controlling AF-2 functionality. The positioning of helix 12 defines the ER alpha (ERα) ligand properties as agonists or antagonists. In contrast, it is still less well defined as to the ligand-dependent regulation of N-terminal AF-1 activity. It has been thought that the action of selective estrogen receptor modulators (SERMs) is mediated by the regulation of a tissue specific AF-1 activity rather than AF-2 activity. However, it is still unclear how SERMs regulate AF-1 activity in a tissue-selective manner. This review presents some recent observations toward information of ERα mediated SERM actions related to the ERα domain functionality, focusing on the following topics. (1) The F-domain, which is connected to helix 12, controls 4-hydroxytamoxifen (4OHT) mediated AF-1 activation associated with the receptor dimerization activity. (2) The zinc-finger property of the DBD for genomic sequence recognition. (3) The novel estrogen responsive genomic DNA element, which contains multiple long-spaced direct-repeats without a palindromic ERE sequence, is differentially recognized by 4OHT and E2 ligand bound ERα transactivation complexes.

Monitoring ligand-mediated helix 12 transitions within the human estrogen receptor α using bipartite tetracysteine display

2020 ◽  
Vol 18 (31) ◽  
pp. 6063-6071
Author(s):  
Ranju Pokhrel ◽  
Tang Tang ◽  
Justin M. Holub
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Α ◽  
Fluorescent Labeling ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Human Estrogen Receptor ◽  
Helix 12

Fluorescent labeling coupled with bipartite tetracysteine display enables the surveillance of ligand-mediated helix 12 transitions within the estrogen receptor α ligand-binding domain.

X-ray crystal structure analysis of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), bound to estrogen receptor alpha ligand binding domain.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15647-e15647
Author(s):  
Sean W. Fanning ◽  
Geoffrey Greene ◽  
Maureen G. Conlan
Keyword(s):  
Breast Cancer ◽  
Crystal Structure ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Ligand Binding Pocket ◽  
X Ray ◽  
Helix 12

e15647 Background: Antiestrogens are a mainstay of treatment for estrogen receptor positive (ER+) breast cancer in both the adjuvant and the advanced/metastatic settings. Elacestrant is a mixed activity selective estrogen receptor (SER) alpha (ERα) antagonist, acting as a SER modulator (SERM) at low doses and a SER degrader (SERD) at high doses. It has shown activity in hormone sensitive wild type (WT) ERα and insensitive estrogen receptor gene 1 (ESR1) mutation-harboring (Y537S and D538G) ERα breast cancer, both in preclinical models and in clinical studies. It also possesses a unique pharmacology compared to other competitive ER antagonists in its ability to cross the blood brain barrier. Competitive ERα antagonists are typically comprised of a core that sits in the ligand binding pocket and an arm that manipulates the structure to achieve SERM or SERD activities. In these molecules, the arm is attached in the same position as the triphenylethylene core of tamoxifen. However, elacestrant possesses a novel site of attachment. As such, we hypothesized that elacestrant adopts an alternative binding orientation in the ERα ligand binding pocket to achieve its unique pharmaceutical profiles. Methods: X-ray crystallography was used to solve a co-crystal structure of elacestrant in complex with WT ERα ligand binding domain to 2Å. Results: Overall, elacestrant promotes the formation of a canonical ERα ligand binding domain antagonist conformation, whereby helix 12 (H12) is docked into the activating function-2 cleft. However, elacestrant adopts a novel vector in the ERα ligand binding pocket that places it in close proximity to helix 12. As a result, it forms a bifurcated hydrogen bond that is not observed in other competitive antiestrogens and samples a chemical space known to increase H12 mobility and induce SERD activity. This novel vector also places it near positions 537 and 538, the two most common sites of somatic mutation. Conclusions: The high-resolution x-ray crystal structure of elacestrant suggests that the unique binding mode it adopts enables novel pharmacology and positions it to achieve potency in the WT and activating somatic ERα mutated breast cancer setting.

scholarly journals The SERM/SERD Bazedoxifene Disrupts ESR1 Helix 12 to Overcome Acquired Hormone Resistance in Breast Cancer Cells

2018 ◽  
Author(s):  
Sean W. Fanning ◽  
Rinath Jeselsohn ◽  
Venkatasubramanian Dharmarajan ◽  
Christopher G. Mayne ◽  
Mostafa Karimi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Hormone Replacement ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Breast Cancers ◽  
Helix 12

AbstractAcquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in theESR1(estrogen receptor alpha (ERα) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER+ breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We find BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show that BZA’s selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.SignificanceBazedoxifene (BZA) is a potent orally available antiestrogen that is clinically approved for use in hormone replacement therapy (DUAVEE). We explore the efficacy of BZA to inhibit activating somatic mutants of ERα that can arise in metastatic breast cancers after prolonged exposure to aromatase inhibitors or tamoxifen therapy. Breast cancer cell line, biophysical, and structural data show that BZA disrupts helix 12 of the ERα ligand binding domain to achieve improved potency against Y537S and D538G somatic mutants compared to 4-hydroxytamoxifen.

scholarly journals G Protein-Coupled Estrogen Receptor 1 (GPER) as a Novel Target for Schizophrenia Drug Treatment

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Danielle S Macêdo ◽  
Lia Lira Olivier Sanders ◽  
Raimunda das Candeias ◽  
Cyntia de Freitas Montenegro ◽  
David Freitas de Lucena ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptors ◽  
G Protein ◽  
Brain Inflammation ◽  
Antipsychotic Treatment ◽  
New Class ◽  
Estrogen Receptor Modulators ◽  
Novel Target ◽  
G Protein Coupled ◽  
Estrogen Receptor 1

Abstract The observation that a person’s sex influences the onset age of schizophrenia, the course of the disease, and antipsychotic treatment response suggests a possible role for estrogen receptors in the pathophysiology of schizophrenia. Indeed, treatment with adjunctive estrogen or selective estrogen receptor modulators (SERMs) are known to reduce schizophrenia symptoms. While estrogen receptors (ER)α and ERβ have been studied, a third and more recently discovered estrogen receptor, the G protein-coupled estrogen receptor 1 (GPER), has been largely neglected. GPER is a membrane receptor that regulates non-genomic estrogen functions, such as the modulation of emotion and inflammatory response. This review discusses the possible role of GPER in brain impairments seen in schizophrenia and in its potential as a therapeutic target. We conducted a comprehensive literature search in the PubMed/MEDLINE database, using the following search terms: “Schizophrenia,” “Psychosis,” “GPER1 protein,” “Estrogen receptors,” “SERMS,” “GPER1 agonism, “Behavioral symptoms,” “Brain Inflammation.” Studies involving GPER in schizophrenia, whether preclinical or human studies, have been scarce, but the results are encouraging. Agonism of the GPER receptor could prove to be an essential mechanism of action for a new class of “anti-schizophrenia” drugs.

Estrogen Receptor Modulators

2021 ◽  
pp. 1-74
Author(s):  
Carlo I. Rosales ◽  
Lauren M. Gutgesell ◽  
Kiira M. Ratia ◽  
Gregory R.J. Thatcher
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Modulators ◽  
Receptor Modulators
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