Different positioning of the ligand-binding domain helix 12 and the F domain of the estrogen receptor accounts for functional differences between agonists and antagonists

The EMBO Journal
Mark NicholsA F Stewart

Abstract

The estrogen receptor is capable of binding a diverse set of ligands that are broadly categorized as agonists or antagonists, depending on their abilities to induce or interfere with transcriptional responsiveness. We show, using a fusion protein assay for ligand-binding which does not rely on transcriptional responsiveness, that agonists and antagonists differently position the C-terminus of the ligand-binding domain (helix 12) and the F domain. Upon antagonist binding, the F domain interferes with the fusion protein activity. Mutational disruption of helix 12 alters the position of the F domain, imposing interference after agonist or antagonist binding. Genetically selected inversion mutations where only agonists, but not antagonists, induce interference are similarly reliant on helix 12 and F domain positioning. Our results demonstrate that agonists and antagonists differently position helix 12 and implicate the F domain in mechanisms of antagonist action.

References

Dec 14, 1995·Nature·R L WagnerR J Fletterick
Jun 20, 1995·Proceedings of the National Academy of Sciences of the United States of America·C Logie, A F Stewart
May 9, 1995·Proceedings of the National Academy of Sciences of the United States of America·A MahfoudiW Wahli
Oct 1, 1994·Current Opinion in Biotechnology·D Picard
Feb 1, 1996·Nature Structural Biology·J M WurtzH Gronemeyer
May 1, 1996·Molecular Medicine Today·D A Tonetti, V C Jordan
Oct 1, 1996·Molecular Endocrinology·K B HorwitzL Tung
Oct 24, 1997·Nature·A M BrzozowskiM Carlquist

❮ Previous
Next ❯

Citations

Jun 16, 2009·Breast Cancer Research and Treatment·Mark NicholsKenneth S McCarty
Mar 26, 2008·Endocrine·Debra F Skafar, Changqing Zhao
May 16, 2000·Biochemical Pharmacology·K Graumann, A Jungbauer
Dec 12, 2002·Steroids·Deborah A Lannigan
Jun 26, 1998·Current Opinion in Cell Biology·D Moras, H Gronemeyer
Dec 22, 1999·Current Opinion in Biotechnology·A Mueller-Fahrnow, U Egner
May 15, 2002·Breast Cancer Research and Treatment·Mark Nichols, Kenneth S McCarty
Jul 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Allen R BuskirkDavid R Liu
Oct 1, 2007·Expert Opinion on Drug Discovery·Eva Estébanez-PerpiñáRobert J Fletterick
Nov 12, 2014·ACS Chemical Biology·Inga M TharunLuc Brunsveld
Dec 8, 2015·Nature Communications·Marcel ScheepstraLuc Brunsveld
Sep 10, 2015·ACS Chemical Biology·Lidia NietoLuc Brunsveld
Jun 5, 2007·The Science of the Total Environment·Otakuye ConroyRobert G Arnold
Apr 10, 2013·Annales d'endocrinologie·Jean-François ArnalFrançoise Lenfant
Jul 18, 2015·Molecular and Cellular Endocrinology·Shivali R Patel, Debra F Skafar
Feb 24, 2001·Home Health Care Services Quarterly·L Goforth
Mar 1, 2005·Chemistry & Biology·Allen R Buskirk, David R Liu
Apr 11, 2018·The Journal of Biological Chemistry·Yukitomo Arao, Kenneth S Korach
Aug 28, 2004·Molecular Endocrinology·Behnom Farboud, Martin L Privalsky
Mar 18, 2000·The Journal of Biological Chemistry·A ChauchereauH Loosfelt
Jun 25, 2005·American Journal of Respiratory and Critical Care Medicine·D Robin TaylorG Peter Herbison
Jan 19, 2010·Journal of Environmental Monitoring : JEM·LeeAnn Racz, Ramesh K Goel
Feb 21, 2014·Molecular Endocrinology·P C T SouzaI Polikarpov
Feb 9, 2018·Endocrinology·Bharti Jaiswal, Ashish Gupta
May 26, 2017·Physiological Reviews·Jean-Francois ArnalJohn Katzenellenbogen
Oct 3, 2001·Physiological Reviews·S NilssonJ A Gustafsson

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.