Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Endocrinology. 2021 Jul 1;162(7). doi: 10.1210/endocr/bqab051.
The thyroid-stimulating hormone receptor (TSHR) is a G-protein-coupled receptor group A family member with 7 transmembrane helices. We generated 3 new models of its entire transmembrane region using a 600 ns molecular simulation. The simulation started from our previously published model, which we have now revised by also modeling the intracellular loops and the C-terminal tail, adding internal waters and embedding it into a lipid bilayer with a water layer and with ions added to complete the system. We have named this model TSHR-TMD-TRIO since 3 representative dominant structures were then extracted from the simulation trajectory and compared with the original model. These structures each showed small but significant changes in the relative positions of the helices. The 3 models were also used as targets to dock a set of small molecules that are known active compounds including a new TSHR antagonist (BT362), which confirmed the appropriateness of the model with some small molecules showing significant preference for one or other of the structures.
甲状腺刺激激素受体（TSHR）是 G 蛋白偶联受体家族 A 成员，具有 7 个跨膜螺旋。我们使用 600ns 分子模拟生成了其整个跨膜区的 3 个新模型。该模拟从我们之前发表的模型开始，我们现在通过模拟细胞内环和 C 末端尾巴，添加内部水，并将其嵌入含有水层和添加离子的双层脂质中来修正该模型，以完成整个系统。由于从模拟轨迹中提取了 3 个具有代表性的主导结构并与原始模型进行了比较，因此我们将该模型命名为 TSHR-TMD-TRIO。这些结构中每个结构的螺旋相对位置都发生了微小但显著的变化。还将这 3 个模型用作一组小分子的对接靶标，这些小分子已知是活性化合物，包括一种新的 TSHR 拮抗剂（BT362），这证实了模型的合理性，一些小分子对一种或另一种结构表现出明显的偏好。
