Structures of androgen receptor bound with ligands: advancing understanding of biological functions and drug discovery

ABSTRACT

Introduction: Androgen receptor (AR) is a ligand-dependent transcription factor and a member of the nuclear receptor superfamily. It plays a vital role in male sexual development and regulates gene expression in various tissues, including prostate. Androgens are compounds that exert their biological effects via interaction with AR. Binding of androgens to AR initiates conformational changes in AR that affect binding of co-regulator proteins and DNA. AR agonists and antagonists are widely used in a variety of clinical applications (i.e. hypogonadism and prostate cancer therapy).

Areas covered: This review provides a close look at structures of AR-ligand complexes and mutations in the receptor that have been revealed, discusses current challenges in the field, and sheds light on future directions.

Expert opinion: AR is one of the primary targets for the treatment of prostate cancer, as AR antagonists inhibit prostate cancer growth. However, these drugs are not effective for long-term treatment and lead to castration-resistant prostate cancer. The structures of AR-ligand complexes are an invaluable scientific asset that enhances our understanding of biological functions and mechanisms of androgenic and anti-androgenic chemicals as well as promotes the discovery of superior drug candidates.

KEYWORDS:

• Androgen receptor
• dihydrotestosterone
• endocrine disruptors
• endocrine receptor
• testosterone

Article highlights

• AR is a member of the nuclear receptor superfamily and one of the primary targets for treatment of prostate cancer.

• AR gene has different splice forms. AR protein has different functional domains. Detailed structural features of AR were reviewed.

• Molecular mechanisms of AR actions were discussed.

• Challenges in crystallization of AR with antagonists were prospected.

• Structures of AR-agonists were compared with AR-antagonists.

• Various mutants in AR were reviewed.

This box summarizes key points contained in the article.

Declaration of interest

This research was supported, in part, by an appointment to the Research Participation Program at the National Center for Toxicological Research (SD Sakkiah and HW Ng) administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. All authors have been supported by internal funding from the Food and Drug Administration (E074501). The findings and conclusions in this article have not been formally disseminated by the US Food and Drug Administration (FDA) and should not be construed to represent the FDA determination or policy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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