Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 Å resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.

法尼醇X受体（FXR）被认为是治疗几种肝脏疾病（例如原发性胆管性胆管炎（PBC）和原发性硬化性胆管炎（PSC））的潜在靶标。Tropifexor是一种高效的非甾体FXR激动剂，已进入PBC患者的II期临床试验。临床试验表明，托吡昔芬改善了肝病患者的血清标志物，并降低了副作用，如瘙痒可能与TGR5激活有关。但是，对托吡索的效力和选择性的分子机制仍不清楚。在这项研究中，通过等温滴定量热法（ITC）测定了FXR和托吡昔洛的结合亲和力。FXR / tropifexor配合物的晶体结构确定为2。7Å分辨率解释了托吡非索与FXR-LBD结合的分子机理。与其他FXR /激动剂结构的结构比较揭示了FXR /托吡咯结构中的构象变化。此外，TGR5 /托吡昔洛的结构重叠表明托吡昔洛与TGR5之间的位阻可能是托吡昔洛对TGR5产生阳imp的可能解释。总体而言，我们的分析可能会提供对托吡昔洛与FXR-LBD结合的分子机制的了解，并解释了托吡昔洛对FXR与TGR5的高选择性。此外，TGR5 /托吡昔洛的结构重叠表明托吡昔洛与TGR5之间的位阻可能是托吡昔洛对TGR5产生阳imp的可能解释。总体而言，我们的分析可能会提供对托吡昔洛与FXR-LBD结合的分子机制的了解，并解释了托吡昔洛对FXR与TGR5的高选择性。此外，TGR5 /托吡昔洛的结构重叠表明托吡昔洛与TGR5之间的位阻可能是托吡昔洛对TGR5产生阳imp的可能解释。总体而言，我们的分析可能会提供对托吡昔洛与FXR-LBD结合的分子机制的了解，并解释了托吡昔洛对FXR与TGR5的高选择性。