Computational model of the full-length TSH receptor

The receptor for thyroid stimulating hormone (TSHR), a GPCR, is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have run a 1000ns Molecular Dynamic simulation on a model of the entire TSHR generated by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linking region (LR), known more commonly as the \"hinge region\", showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. ..., The cooordinates were generated by judiciously chosen translation and rotation of the ecodomain model to merge it with the TMD model., The file is in the classic PDB format - any molecular graphics program (e.g., VMD) can display it.

促甲状腺激素受体（thyroid stimulating hormone receptor, TSHR）属于G蛋白偶联受体（G protein-coupled receptor, GPCR），作为由刺激性促甲状腺激素抗体诱发的自身免疫性甲状腺功能亢进症（格雷夫斯病，Graves' disease）的核心抗原，具有极高的研究价值。截至目前，仅解析了TSHR胞外区的单个结构域的晶体结构。本研究先通过人工智能获取受体胞外区，并结合我们近期构建的跨膜结构域同源模型拼接得到完整TSHR模型；随后将该模型嵌入脂质膜，以水和抗衡离子完成溶剂化处理，进而开展了1000纳秒的分子动力学模拟。模拟结果显示，跨膜结构域与富亮氨酸结构域的构象极为稳定，而通常被称为"铰链区"的连接区域（linking region, LR）则呈现出显著的柔性，可形成多种瞬时二级结构元件。此外，富亮氨酸结构域与受体其余部分的相对取向也存在可变性。……，整套结构坐标通过对胞外结构域模型进行合理选择的平移与旋转操作，将其与跨膜结构域模型拼接得到。本数据集采用经典的PDB格式存储，可通过任意分子可视化软件（如VMD）进行展示。