Discovered as a modulator of the toxic response to environmental pollutants, aryl hydrocarbon receptor (AhR) has recently gained attention for its involvement in various physiological and pathological pathways. AhR is a ligand‐dependent transcription factor activated by a large array of chemical compounds, which include metabolites of l‐tryptophan (l‐Trp) catabolism as endogenous ligands of the receptor. Among these, 2‐(1′H‐indole‐3′‐carbonyl)thiazole‐4‐carboxylic acid methyl ester (ITE) has attracted interest in the scientific community, being endowed with nontoxic, immunomodulatory, and anticancer AhR‐mediated functions. So far, no information about the binding mode and interactions of ITE with AhR is available. In this study, we used docking and molecular dynamics to propose a putative binding mode of ITE into the ligand binding pocket of AhR. Mutagenesis studies were then instrumental in validating the proposed binding mode, identifying His 285 and Tyr 316 as important key residues for ligand‐dependent receptor activation. Finally, a set of ITE analogues was synthesized and tested to further probe molecular interactions of ITE to AhR and characterize the relevance of specific functional groups in the chemical structure for receptor activity.

中文翻译：

---

ITE作为芳烃受体（AhR）激动剂的结合模式和结构-活性关系

芳烃受体（AhR）被发现是对环境污染物的毒性反应的调节剂，最近因其参与各种生理和病理途径而受到关注。AhR是依赖配体的转录因子，可被多种化合物激活，这些化合物包括l-色氨酸（l- Trp）分解代谢产物作为受体的内源性配体。其中，2-（1′H吲哚-3′-羰基）噻唑-4-羧酸甲酯（ITE）在科学界引起了人们的兴趣，具有无毒，免疫调节和抗癌的AhR介导的功能。到目前为止，尚无有关ITE与AhR的绑定模式和交互的信息。在这项研究中，我们使用对接和分子动力学来提出ITE推定的结合模式到AhR的配体结合口袋中。然后诱变研究有助于验证提出的结合模式，将His 285和Tyr 316鉴定为配体依赖性受体激活的重要关键残基。最后，合成并测试了一组ITE类似物，以进一步探测ITE与AhR的分子相互作用，并表征化学结构中特定官能团与受体活性的相关性。