Access path to the ligand binding pocket may play a role in xenobiotics selection by AhR

Dániel Szöllösi, Áron Erdei, Gergely Gyimesi, C. Magyar, T. Hegedűs

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere0146066
JournalPLoS One
Volume11
Issue number1
DOIs
Publication statusPublished - Jan 4 2016

Fingerprint

Aryl Hydrocarbon Receptors
Xenobiotics
xenobiotics
hydrocarbons
Ligands
receptors
Computer Simulation
Molecules
Pharmaceutical Preparations
drugs
Docks
molecular dynamics
Drug Design
Molecular Dynamics Simulation
Metabolism
pharmacokinetics
Molecular dynamics
ligands
oxidation
Oxidation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Access path to the ligand binding pocket may play a role in xenobiotics selection by AhR. / Szöllösi, Dániel; Erdei, Áron; Gyimesi, Gergely; Magyar, C.; Hegedűs, T.

In: PLoS One, Vol. 11, No. 1, e0146066, 04.01.2016.

Research output: Contribution to journalArticle

Szöllösi, Dániel ; Erdei, Áron ; Gyimesi, Gergely ; Magyar, C. ; Hegedűs, T. / Access path to the ligand binding pocket may play a role in xenobiotics selection by AhR. In: PLoS One. 2016 ; Vol. 11, No. 1.
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