Abstract
Hydroxyflutamide (HF), an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR). However, a drug resistance problem appears after about one year’s treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD) simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA) method have been carried out to analyze the interaction mechanism between HF and wild-type (WT)/mutant ARs. The obtained results indicate that AR helix 12 (H12) plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12). When H12 closes to the AR ligand-binding domain (LBD) like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per-residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF.
Highlights
Prostate cancer (PCa) is one of the main causes of cancer death and the most commonly diagnosed cancer among men worldwide [1,2]
Androgen receptor is a ligand-inducible hormone receptor of the nuclear receptor superfamily [5,6,7], which consists of three major functional domains: an N-terminal domain (NTD), a central DNA binding domain (DBD), and a C-terminal ligand-binding domain (LBD), which is connected to the DBD by a flexible hinge region
The activation function 2 (AF2), a hydrophobic surface composed of helix 3 (H3), helix 4 (H4), and helix 12 (H12), located in the LBD, is ligand-dependent [8]
Summary
Prostate cancer (PCa) is one of the main causes of cancer death and the most commonly diagnosed cancer among men worldwide [1,2]. Plenty of studies have shown that androgen receptor (AR) is a key signaling pathway leading to the emergence of PCa [3]. Androgen receptor is a vital target for the treatment of PCa [4]. Androgen receptor is a ligand-inducible hormone receptor of the nuclear receptor superfamily [5,6,7], which consists of three major functional domains: an N-terminal domain (NTD), a central DNA binding domain (DBD), and a C-terminal ligand-binding domain (LBD), which is connected to the DBD by a flexible hinge region. The activation function 2 (AF2), a hydrophobic surface composed of helix 3 (H3), helix 4 (H4), and helix 12 (H12), located in the LBD, is ligand-dependent [8]. AR is mainly located in the cytoplasm of the prostate cell, combining with heat shock proteins (HSPs) [9]
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