Ligand binding and functional selectivity of L-tryptophan metabolites at the mouse aryl hydrocarbon receptor (mAhR).
The aryl hydrocarbon receptor (AhR) is a nuclear receptor regulating a wide range of biological and toxicological effects. Metabolites of L-tryptophan are able to bind and activate AhR, providing a link between tryptophan catabolism and a novel mechanism of protective tolerance, referred to as "disease tolerance". The notion that pharmacologic modulation of genes associated with endotoxin tolerance would be beneficial in clinical settings dominated by acute hyperinflammatory responses to infection thrusts AhR into the limelight as an interesting druggable target. Combining homology modeling, docking studies, and molecular dynamic simulations with mutagenesis experiments and gene profiling, in this work we report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and two different L-tryptophan metabolites, namely L-Kynurenine and FICZ (6-formylindolo[3,2-b]carbazole), are able to bind to mAhR, exploiting different key interactions with distinct set of fingerprint residues. As a result, they stabilize different conformations of mAhR that, in turn, selectively regulate downstream signaling and transcription of specific target genes. Collectively, these results open new avenues for the design and development of selective AhR modulators that, by targeting specific receptor conformations associated with specific AhR functions, may offer novel therapeutic opportunities in infectious diseases and other morbidity that may be associated with the receptor.
Department of Pharmaceutical Sciences and ‡Department of Experimental Medicine, Università di Perugia , via del Liceo 1, 06123 Perugia, Italy.
Roberto
R
Nuti
Marco
M
Gargaro
Davide
D
Matino
Daniela
D
Dolciami
Ursula
U
Grohmann
Paolo
P
Puccetti
Francesca
F
Fallarino
Antonio
A
Macchiarulo
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D059467:Transcriptome; D014364:Tryptophan / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D007737:Kynurenine; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D014364:Tryptophan; C111855:6-formylindolo(3,2-b)carbazole; C484722:Ahr protein, mouse