Modeling of the aryl hydrocarbon receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands.
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and interspecies differences in ligand binding using molecular docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes.
Bisson
William H
WH
Cancer Biology Laboratory, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA.
Koch
Daniel C
DC
O'Donnell
Edmond F
EF
Khalil
Sammy M
SM
Kerkvliet
Nancy I
NI
Tanguay
Robert L
RL
Abagyan
Ruben
R
Kolluri
Siva Kumar
SK
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014584:User-Computer Interface
D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon