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PMID: 21981577 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

New aryl hydrocarbon receptor homology model targeted to improve docking reliability.

Journal of chemical information and modeling ·Vol. 51 ·No. 11 ·2011-11-28 ·Pages 2868-81

Motto I, Bordogna A, Soshilov AA, Denison MS, Bonati L

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent, basic helix-loop-helix Per-ARNT-Sim (PAS) containing transcription factor that can bind and be activated by structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). As no experimentally determined structures of the AhR ligand binding domain (LBD) are available and previous homology models were only derived from apo template structures, we developed a new model based on holo X-ray structures of the hypoxia-inducible factor 2α (HIF-2α) PAS B domain, targeted to improve the accuracy of the binding site for molecular docking applications. We experimentally confirmed the ability of two HIF-2α crystallographic ligands to bind to the mAhR with relatively high affinity and demonstrated that they are AhR agonists, thus justifying the use of the holo HIF-2α structures as templates. A specific modeling/docking approach was proposed to predict the binding modes of AhR ligands in the modeled LBD. It was validated by comparison of the calculated and the experimental binding affinities of active THS ligands and TCDD for the mAhR and by functional activity analysis using several mAhR mutants generated on the basis of the modeling results. Finally the ability of the proposed approach to reproduce the different affinities of TCDD for AhRs of different species was confirmed, and a first test of its reliability in virtual screening is carried out by analyzing the correlation between the calculated and experimental binding affinities of a set of 14 PCDDs.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/chemistry,genetics,metabolism Binding Sites Binding, Competitive COS Cells Chlorocebus aethiops Computational Biology/methods Crystallography, X-Ray Electrophoretic Mobility Shift Assay Gene Expression Helix-Loop-Helix Motifs Humans Ligands Models, Molecular Mutagenesis, Site-Directed Mutation Plasmids Polychlorinated Dibenzodioxins/chemistry,metabolism Protein Binding Receptors, Aryl Hydrocarbon/agonists,chemistry,genetics,metabolism Recombinant Proteins/chemistry,genetics,metabolism Transfection
Chemicals
Basic Helix-Loop-Helix Transcription Factors Ligands Polychlorinated Dibenzodioxins Receptors, Aryl Hydrocarbon Recombinant Proteins endothelial PAS domain-containing protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Motto Ilaria
Dipartimento di Scienze dell'Ambiente e del Territorio, Università degli Studi di Milano-Bicocca, Piazza della Scienza 1, 20126 Milano, Italy.
Bordogna Annalisa
Soshilov Anatoly A
Denison Michael S
Bonati Laura
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Article Info
Journal
Journal of chemical information and modeling
Abbr.
J Chem Inf Model
ISSN
1549-960X
DOI
10.1021/ci2001617
Published
2011-11-28
Epub
2011-00-02
Pages
2868-81
Language
English
Region
United States
NLM ID
101230060
PMCID
PMC3263330
Subset
IM
Grants
NIEHS NIH HHS · R01 ES007685-12A1 · United States
NIEHS NIH HHS · ES007685 · United States
NIEHS NIH HHS · P42 ES004699 · United States
NIEHS NIH HHS · P42 ES004699-25 · United States
NIEHS NIH HHS · ES004699 · United States
NIEHS NIH HHS · R01 ES007685 · United States
External Links
PubMed source DOI: 10.1021/ci2001617 PMC Full Text View journal details
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