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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2868-2881 |
| Number of pages | 14 |
| Journal | Journal of Chemical Information and Modeling |
| Volume | 51 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 28 2011 |
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ASJC Scopus subject areas
- Chemistry(all)
- Chemical Engineering(all)
- Computer Science Applications
- Library and Information Sciences
Cite this
New aryl hydrocarbon receptor homology model targeted to improve docking reliability. / Motto, Ilaria; Bordogna, Annalisa; Soshilov, Anatoly A.; Denison, Michael S.; Bonati, Laura.
In: Journal of Chemical Information and Modeling, Vol. 51, No. 11, 28.11.2011, p. 2868-2881.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - New aryl hydrocarbon receptor homology model targeted to improve docking reliability
AU - Motto, Ilaria
AU - Bordogna, Annalisa
AU - Soshilov, Anatoly A.
AU - Denison, Michael S.
AU - Bonati, Laura
PY - 2011/11/28
Y1 - 2011/11/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=82355168493&partnerID=8YFLogxK
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U2 - 10.1021/ci2001617
DO - 10.1021/ci2001617
M3 - Article
C2 - 21981577
AN - SCOPUS:82355168493
VL - 51
SP - 2868
EP - 2881
JO - Journal of Chemical Information and Computer Sciences
JF - Journal of Chemical Information and Computer Sciences
SN - 0095-2338
IS - 11
ER -