+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Ligand unbinding from the estrogen receptor: a computational study of pathways and ligand specificity



Ligand unbinding from the estrogen receptor: a computational study of pathways and ligand specificity



Proteins 77(4): 842-856



The estrogen receptor (ER) belongs to the nuclear receptor superfamily, whose members regulate important cellular events like development and metabolism. The ER functions as a transcription regulator and can be activated on ligand binding. Consequently, ligand binding and unbinding constitute fundamental processes in the regulation of genes. Even though both biochemical and structural data of ER are available, the actual mechanism of the ligand binding/unbinding remains elusive. We have performed computational studies on the unbinding mechanism of ERalpha and ERbeta, in the presence of cofactors and with ligands ranging from agonist to a full antagonist. Our results show that agonists or selective ER modulators can dissociate from the receptor through multiple pathways with minor effect on the receptor structure, whereas an antagonist requires larger conformational changes. Furthermore, a specific receptor/ligand combination can exhibit a pathway preference depending on character and conformation of both parts. Hence, it is possible that the binding/unbinding mechanism can explain ligand subtype specificity and thus have an impact in drug discovery.

(PDF emailed within 0-6 h: $19.90)

Accession: 054124691

Download citation: RISBibTeXText

PMID: 19626711

DOI: 10.1002/prot.22503


Related references

Computational insights into the mechanism of ligand unbinding and selectivity of estrogen receptors. Journal of Physical Chemistry. B 113(30): 10436-10444, 2009

Multiple Ligand Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore. Biophysical Journal 112(4): 620-629, 2017

An estrogen receptor-alpha knock-in mutation provides evidence of ligand-independent signaling and allows modulation of ligand-induced pathways in vivo. Endocrinology 149(6): 2970-2979, 2008

Computational Study of Protein-Ligand Unbinding for Enzyme Engineering. Frontiers in Chemistry 6: 650-650, 2019

Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations. European Biophysics Journal 38(2): 185-198, 2008

A computational study on ligand assisted vs. ligand participation mechanisms for CO2 hydrogenation: importance of bifunctional ligand based catalysts. Physical Chemistry Chemical Physics 2019, 2019

Determinants of ligand specificity of estrogen receptor-a: estrogen versus androgen discrimination. The Journal of Biological Chemistry 273: 3-9, 1998

Determinants of ligand specificity of estrogen receptor-alpha: estrogen versus androgen discrimination. Journal of Biological Chemistry 273(2): 693-699, 1998

Site-directed estrogen receptor antibodies stabilize 4-hydroxytamoxifen ligand, but not estradiol, and indicate ligand-specific differences in the recognition of estrogen response element DNA in vitro. Steroids 61(5): 278-289, 1996

ART-RRT: As-Rigid-As-Possible exploration of ligand unbinding pathways. Journal of Computational Chemistry 39(11): 665-678, 2018

Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Molecular Endocrinology 9(2): 208-218, 1995

Reversible photo-unbinding of AChR ligand allows study of receptor mobility at the neuromuscular junction in vivo. Society for Neuroscience Abstracts 26(1-2): Abstract No -16 9, 2000

Conversion of a human low-density lipoprotein receptor ligand-binding repeat to a virus receptor: Identification of residues important for ligand specificity. Proceedings of the National Academy of Sciences of the United States of America 95(15): 8467-8472, 1998

Consensus Computational Ligand-Based Design for the Identification of Novel Modulators of Human Estrogen Receptor Alpha. Molecular Informatics 31(3-4): 246-258, 2012

Ligand-dependent switching of ubiquitin-proteasome pathways for estrogen receptor. EMBO (European Molecular Biology Organization) Journal 23(24): 4813-4823, 2004