Identification of the Ah-receptor structural determinants for ligand preferences.
The aryl hydrocarbon receptor (AHR) is a transcription factor that responds to diverse ligands and plays a critical role in toxicology, immune function, and cardiovascular physiology. The structural basis of the AHR for ligand promiscuity and preferences is critical for understanding AHR function. Based on the structure of a closely related protein HIF2α, we modeled the AHR ligand binding domain (LBD) bound to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo(a)pyrene (BaP) and identified residues that control ligand preferences by shape and H-bond potential. Mutations to these residues, particularly Q377 and G298, resulted in robust and opposite changes in the potency of TCDD and BaP and up to a 20-fold change in the ratio of TCDD/BaP efficacy. The model also revealed a flexible "belt" structure; molecular dynamic (MD) simulation suggested that the "belt" and several other structural elements in the AHR-LBD are more flexible than HIF2α and likely contribute to ligand promiscuity. Molecular docking of TCDD congeners to a model of human AHR-LBD ranks their binding affinity similar to experimental ranking of their toxicity. Our study reveals key structural basis for prediction of toxicity and understanding the AHR signaling through diverse ligands.
McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin 53706, USA. xing@oncology.wisc.edu
Yongna
Y
Xing
Manabu
M
Nukaya
Kenneth A
KA
Satyshur
Li
L
Jiang
Vitali
V
Stanevich
Elif Nihal
EN
Korkmaz
Lisa
L
Burdette
Gregory D
GD
Kennedy
Qiang
Q
Cui
Christopher A
CA
Bradfield
D000595:Amino Acid Sequence; D001564:Benzo(a)pyrene / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D011487:Protein Conformation; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene