title: Effects of HO-/MeO-PBDEs on androgen receptor: in vitro investigation and helix 12-involved MD simulation.
abstract: Hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) have received increasing attention for their potential endocrine disrupting activities and widely environmental distribution. However, little information is available for the anti-androgenic activities, and the molecular mechanism of interactions with androgen receptor (AR) is not fully understood. In the present study, cell line assay and computational simulation were integrated to systematically explore the molecular mechanism of interactions between chemicals and AR. The metabolites with similar molecular structures exhibited different anti-androgenic activity while none of them showed androgenic activity. According to the multisystem molecular dynamics simulation, minute differences in the structure of ligands induced dramatic different conformational transition of AR-ligand binding domain (LBD). The Helix12 (H12) component of active ligands occupied AR-LBD could become stable, but this component continued to fluctuate in inactive ligands occupied AR-LBD. Settling time and reposition of H12 obtained in dynamics process are important factors governing anti-androgenic activities. The related settling times were characteristic of anti-androgenic potencies of the tested chemicals. Overall, in our study, the stable reposition of H12 is characterized as a computational mark for identifying AR antagonists from PBDE metabolites, or even other various environmental pollutants.
authors.affiliation: State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University , Nanjing 210023, PR China.
authors.forename: Xiaoxiang
authors.initials: X
authors.lastname: Wang
authors.forename: Huaiyu
authors.initials: H
authors.lastname: Yang
authors.forename: Xinxin
authors.initials: X
authors.lastname: Hu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiansen
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yu
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D002460:Cell Line; D005485:Flutamide / Q000494:pharmacology; D017930:Genes, Reporter; D055768:Halogenated Diphenyl Ethers / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D059002:Androgen Receptor Antagonists; D055768:Halogenated Diphenyl Ethers; D008024:Ligands; D011944:Receptors, Androgen; D005485:Flutamide