Androgen Receptor

[Michael Scally MD]

Monks DA, Holmes MM. Androgen receptors and muscle: a key mechanism underlying life history trade-offs. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. Androgen receptors and muscle: a key mechanism underlying life history trade-offs

Sexual dimorphism in skeletal muscle is prominent in mammals, with males typically having larger and stronger muscles than females. Furthermore, neuromuscular systems with sexual functions are remarkably sexually dimorphic in a wide variety of vertebrates. Endocrine mechanisms are of central importance for sexual differentiation of these traits, and anabolic actions of gonadal testosterone have been intensively studied.

Here we review the relationship between androgen receptor (AR) and sexual differentiation of neuromuscular systems. We focus our review on the hypotheses that sexual dimorphism and androgen responsiveness of neuromuscular systems is a function of the amount of AR expressed by muscle and that AR in muscle is a key mechanism on which evolution acts to shape individual and species differences in reproductive behavior.

 

[Michael Scally MD]

A Magic Drug Target: Androgen Receptor

Androgen receptor (AR) is closely associated with a group of hormone-related diseases including the cancers of prostate, breast, ovary, pancreas, etc and anabolic deficiencies such as muscle atrophy and osteoporosis.

Depending on the specific type and stage of the diseases, AR ligands including not only antagonists but also agonists and modulators are considered as potential therapeutics, which makes AR an extremely interesting drug target.

Here, we at first review the current understandings on the structural characteristics of AR, and then address why and how AR is investigated as a drug target for the relevant diseases and summarize the representative antagonists and agonists targeting five prospective small molecule binding sites at AR, including ligand-binding pocket, activation function-2 site, binding function-3 site, DNA-binding domain, and N-terminal domain, providing recent insights from a target and drug development view.

Further comprehensive studies on AR and AR ligands would bring fruitful information and push the therapy of AR relevant diseases forward.

Li D, Zhou W, Pang J, et al. A magic drug target: Androgen receptor. Medicinal research reviews 2018. https://onlinelibrary.wiley.com/doi/abs/10.1002/med.21558

 

[Michael Scally MD]

Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis.

Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases.

In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 microM and 4.92 microM, respectively, which are even lower than that of enzalutamide (Enz, IC50 = 13.87 microM), a marketed second-generation AR antagonist.

Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different.

In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.

Zhou W, Duan M, Fu W, et al. Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays. Genomics, proteomics & bioinformatics 2019. https://www.sciencedirect.com/science/article/pii/S1672022919300014?via=ihub

 

[Millard]

"In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases doping products for sports."

 

[Michael Scally MD]

Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor

Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription producing a diverse range of biological effects.

Anti-androgens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized.

Therefore, in this study, multiple 1 µs molecular dynamics (MD), docking simulations and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands.

We characterized the mechanism of the ligand entry/exit and found that Helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists.

Agonist binding to AR increases mobility of residues at allosteric sites and co-activator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding.

These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.

Azhagiya Singam ER, Tachachartvanich P, La Merrill MA, Smith MT, Durkin KA. Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor. The Journal of Physical Chemistry B 2019. https://doi.org/10.1021/acs.jpcb.9b05654

 

[Michael Scally MD]

Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes

Highlights
· Full-length AR follows a unique head-to-head and tail-to-tail dimerization
· AR LBD and DBD and NTD all form the dimerization interface
· AR interacts with one SRC-3 and one p300
· AR N-terminal domain plays a major role in recruiting SRC-3 and p300

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity.

In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations.

Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment.

The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.

Yu X, Yi P, Hamilton RA, et al. Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes. Molecular Cell 2020. Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes - ScienceDirect

 

[Michael Scally MD]

Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes

Highlights
· Full-length AR follows a unique head-to-head and tail-to-tail dimerization
· AR LBD and DBD and NTD all form the dimerization interface
· AR interacts with one SRC-3 and one p300
· AR N-terminal domain plays a major role in recruiting SRC-3 and p300

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity.

In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations.

Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment.

The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.

Yu X, Yi P, Hamilton RA, et al. Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes. Molecular Cell 2020. Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes - ScienceDirect

3D Androgen Receptor Structure Opens Door to Potential Prostate Cancer Therapies
3D Androgen Receptor Structure Opens Door to Potential Prostate Cancer Therapies

Looking to have a better understanding of how the androgen receptor works in prostate cancer, researchers at Baylor College of Medicine conducted comprehensive studies of the 3-D structure of the receptor. Their findings unveiled the structure of a site on the receptor, the N-terminal domain, where it interacts with activity-enhancing coactivators that together regulate gene expression that drives prostate cancer.

The study, “Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes,” published in Molecular Cell, offers new insights for the design of future treatments for this devastating condition, according to the team.

“Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity. In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations,” write the investigators.

...


The researchers discovered that the N-terminal domain at the beginning of the androgen receptor is where the coactivators bind, activating the complex that drives prostate cancer. This finding was in marked contrast with what the same researchers had discovered for the estrogen receptor, which is a major driver of breast cancer.

The androgen and the estrogen receptors belong to the same family of steroid nuclear receptors and share similar 3-D structures. However, despite having general structural similarities, in the estrogen receptor the coactivators bind not to the N-terminal domain at the beginning of the molecule, but to the C-terminal domain at the end of the molecule. This finding has important implications generating drugs for cancer treatment, explains O’Malley.

“The androgen receptor drug inhibitors that are currently available for prostate cancer treatment bind to the C-terminal domain, which we found is not the main interactive site of the androgen receptor,” he said. “Our work strongly supports further studies to determine the effect that drugs directed at the androgen receptor’s N-terminal domain have on prostate cancer growth.”