scholarly journals Molecular Basis for the Subtype Discrimination of the Estrogen Receptor-β-Selective Ligand, Diarylpropionitrile

2003 ◽  
Vol 17 (2) ◽  
pp. 247-258 ◽  
Author(s):  
Jun Sun ◽  
Jerome Baudry ◽  
John A. Katzenellenbogen ◽  
Benita S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Molecular Basis ◽  
Binding Pocket ◽  
Ligand Binding Pocket ◽  
Selective Ligand ◽  
Selective Ligands ◽  
Human Estrogen Receptor ◽  
Subtype Selective ◽  
Selective Character

Abstract Although the two subtypes of the human estrogen receptor (ER), ERα and ERβ, share only 56% amino acid sequence identity in their ligand binding domain (LBD), the residues that surround the ligand are nearly identical; nevertheless, subtype-selective ligands are known. To understand the molecular basis by which diarylpropionitrile (DPN), an ERβ-selective ligand, is able to discriminate between the two ERs, we examined its activity on ER mutants and chimeric constructs generated by DNA shuffling. The N-terminal region of the ERβ LBD (through helix 6) appears to be fully responsible for the ERβ selectivity of DPN. In fact, a single ERα point mutation (L384M) was largely sufficient to switch the DPN response of this ER to that of the ERβ type, but residues in helix 3 are also important in achieving the full ERβ selectivity of DPN. Using molecular modeling, we found an energetically favorable fit for the S-DPN enantiomer in ERβ, in which the proximal phenol mimics the A ring of estradiol, and the nitrile engages in stabilizing interactions with residues in the ligand-binding pocket of ERβ. Our findings highlight that a limited number of critical interactions of DPN with the ERβ ligand-binding pocket underlie its ER subtype-selective character.

The nature of the ligand-binding pocket of estrogen receptor alpha and beta: The search for subtype-selective ligands and implications for the prediction of estrogenic activity

2003 ◽  
Vol 75 (11-12) ◽  
pp. 2397-2403 ◽  
Author(s):  
J. A. Katzenellenbogen ◽  
R. Muthyala ◽  
B. S. Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Estrogen Receptor Alpha ◽  
Estrogenic Activity ◽  
Binding Pocket ◽  
Receptor Alpha ◽  
Subtype Selectivity ◽  
Selective Ligands ◽  
Binding Pockets ◽  
Subtype Selective

The ligand-binding pockets of estrogen receptor alpha and beta (ERα and ERβ) appear to have subpockets of different size and flexibility. To find ligands that will discriminate between the two ER subtypes on the basis of affinity or efficacy, we have prepared compounds of varying size, shape and structure. We have evaluated the binding affinity of these compounds and their potency and efficacy as transcriptional activators through ERα and ERβ. In this manner, we have identified a number of ligands that show pronounced ER subtype selectivity. These studies also highlight the eclectic structure–activity relationships of estrogens and the challenges inherent in developing computational methods for the prediction of estrogenic activity.

scholarly journals Dual-mechanism estrogen receptor inhibitors expand the repertoire of anti-hormone therapy for breast cancer

2020 ◽  
Author(s):  
Jian Min ◽  
Jerome C. Nwachukwu ◽  
Sathish Srinivasan ◽  
Erumbi S. Rangarajan ◽  
Charles C. Nettles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Ligand Binding ◽  
Targeted Therapies ◽  
De Novo ◽  
Binding Pocket ◽  
Side Chain ◽  
Ligand Binding Pocket ◽  
Single Mechanism ◽  
Dual Mechanism

ABSTRACTTamoxifen and fulvestrant are currently two major approved estrogen receptor-α (ER)-targeted therapies for breast cancer, but resistance to their antagonistic actions often develops. Efforts to improve ER-targeted therapies have relied upon a single mechanism, where ligands with a single side chain on the ligand core that extends outward from the ligand binding pocket to directly displace helix (h)12 in the ER ligand-binding domain (LBD), blocking the LBD interaction with transcriptional coactivators that drive proliferation. Here, we describe ER inhibitors that block estrogen-induced proliferation through two distinct structural mechanisms by combining a side chain for direct antagonism with a bulky chemical group that causes indirect antagonism by distorting structural epitopes inside the ligand binding pocket. These dual-mechanism ER inhibitors (DMERIs) fully antagonize the proliferation of wild type ER-positive breast cancer cells and cells that have become resistant to tamoxifen and fulvestrant through activating ER mutations and de novo mechanisms such as overactive growth factor signaling. Conformational probing studies highlight marked differences that distinguish the dual mechanism inhibitors from current standard of care single-mechanism antiestrogens, and crystallographic analyses reveal that they disrupt the positioning of h11 and h12 in multiple ways. Combining two chemical targeting approaches into a single ligand thus provides a flexible platform for next generation ER-targeted therapies.

Estrogen pyrazoles: defining the pyrazole core structure and the orientation of substituents in the ligand binding pocket of the estrogen receptor

2001 ◽  
Vol 9 (1) ◽  
pp. 141-150 ◽  
Author(s):  
Shaun R Stauffer ◽  
Ying Huang ◽  
Christopher J Coletta ◽  
Rosanna Tedesco ◽  
John A Katzenellenbogen
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Pocket ◽  
Core Structure ◽  
Ligand Binding Pocket

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.

Estrogen Receptor Microarrays:  Subtype-Selective Ligand Binding

2004 ◽  
Vol 126 (15) ◽  
pp. 4754-4755 ◽  
Author(s):  
Sung Hoon Kim ◽  
Anobel Tamrazi ◽  
Kathryn E. Carlson ◽  
Jonathan R. Daniels ◽  
In Young Lee ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Selective Ligand ◽  
Subtype Selective

scholarly journals Suramin Targets the Conserved Ligand-Binding Pocket of Human Raf1 Kinase Inhibitory Protein

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1151
Author(s):  
Chenyun Guo ◽  
Zhihua Wu ◽  
Weiliang Lin ◽  
Hao Xu ◽  
Ting Chang ◽  
...  
Keyword(s):  
Side Effects ◽  
Ligand Binding ◽  
Mapk Pathway ◽  
Regulatory Protein ◽  
Therapeutic Index ◽  
Binding Pocket ◽  
Biological Macromolecules ◽  
Inhibitory Protein ◽  
Ligand Binding Pocket ◽  
Raf1 Kinase

Suramin was initially used to treat African sleeping sickness and has been clinically tested to treat human cancers and HIV infection in the recent years. However, the therapeutic index is low with numerous clinical side-effects, attributed to its diverse interactions with multiple biological macromolecules. Here, we report a novel binding target of suramin, human Raf1 kinase inhibitory protein (hRKIP), which is an important regulatory protein involved in the Ras/Raf1/MEK/ERK (MAPK) signal pathway. Biolayer interference technology showed that suramin had an intermediate affinity for binding hRKIP with a dissociation constant of 23.8 µM. Both nuclear magnetic resonance technology and molecular docking analysis revealed that suramin bound to the conserved ligand-binding pocket of hRKIP, and that residues K113, W173, and Y181 play crucial roles in hRKIP binding suramin. Furthermore, suramin treatment at 160 µM could profoundly increase the ERK phosphorylation level by around 3 times. Our results indicate that suramin binds to hRKIP and prevents hRKIP from binding with hRaf1, thus promoting the MAPK pathway. This work is beneficial to both mechanistically understanding the side-effects of suramin and efficiently improving the clinical applications of suramin.

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