Access Path to the Ligand Binding Pocket May Play a Role in Xenobiotics Selection by AhR

PLoS One. 2016 Jan 4;11(1):e0146066. doi: 10.1371/journal.pone.0146066. eCollection 2016.


Understanding of multidrug binding at the atomic level would facilitate drug design and strategies to modulate drug metabolism, including drug transport, oxidation, and conjugation. Therefore we explored the mechanism of promiscuous binding of small molecules by studying the ligand binding domain, the PAS-B domain of the aryl hydrocarbon receptor (AhR). Because of the low sequence identities of PAS domains to be used for homology modeling, structural features of the widely employed HIF-2α and a more recent suitable template, CLOCK were compared. These structures were used to build AhR PAS-B homology models. We performed molecular dynamics simulations to characterize dynamic properties of the PAS-B domain and the generated conformational ensembles were employed in in silico docking. In order to understand structural and ligand binding features we compared the stability and dynamics of the promiscuous AhR PAS-B to other PAS domains exhibiting specific interactions or no ligand binding function. Our exhaustive in silico binding studies, in which we dock a wide spectrum of ligand molecules to the conformational ensembles, suggest that ligand specificity and selection may be determined not only by the PAS-B domain itself, but also by other parts of AhR and its protein interacting partners. We propose that ligand binding pocket and access channels leading to the pocket play equally important roles in discrimination of endogenous molecules and xenobiotics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Binding Sites
  • CLOCK Proteins / chemistry
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Chemical
  • Models, Molecular
  • Molecular Docking Simulation
  • Multiprotein Complexes
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Aryl Hydrocarbon / chemistry*
  • Receptors, Aryl Hydrocarbon / metabolism
  • Substrate Specificity
  • Xenobiotics / metabolism*


  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Ligands
  • Multiprotein Complexes
  • Receptors, Aryl Hydrocarbon
  • Xenobiotics
  • endothelial PAS domain-containing protein 1
  • CLOCK Proteins
  • Clock protein, mouse

Grants and funding

This work was supported by a Bolyai Fellowship of the Hungarian Academy of Sciences (TH), NKFIH K 111678 (TH), and OTKA NK 100482 (CM). Gergely Gyimesi was funded by the Marie Curie Actions International Fellowship Program (IFP) TransCure (