Department of Molecular Biology, Ariel University, Ariel, Israel.
Department of Computer Sciences, Ariel University, Ariel, Israel.
Front Endocrinol (Lausanne). 2022 May 27;13:895240. doi: 10.3389/fendo.2022.895240. eCollection 2022.
Thyroid hormones (TH), T4 and T3, mediate pro-mitogenic effects in cancer cells through binding the membrane receptor αvβ3 integrin. The deaminated analogue tetrac effectively blocks TH binding to this receptor and prevents their action. While computational data on TH binding to the αvβ3 integrin was published, a comprehensive analysis of additional TH metabolites is lacking.
docking of 26 TH metabolites, including the biologically active thyroid hormones (T3 and T4) and an array of sulfated, deiodinated, deaminated or decarboxylated metabolites, to the αvβ3 receptor binding pocket was performed using DOCK6, based on the three-dimensional representation of the crystallographic structure of the integrin. As the TH binding site upon the integrin is at close proximity to the well-defined RGD binding site, linear and cyclic RGD were included as a reference. Binding energy was calculated for each receptor-ligand complex using Grid score and Amber score with distance movable region protocol.
All TH molecules demonstrated negative free energy, suggesting affinity to the αvβ3 integrin. Notably, based on both Grid and Amber scores sulfated forms of 3,3' T2 (3,3' T2S) and T4 (T4S) demonstrated the highest binding affinity to the integrin, compared to both cyclic RGD and an array of examined TH metabolites. The major thyroid hormones, T3 and T4, showed high affinity to the integrin, which was superior to that of linear RGD. For all hormone metabolites, decarboxylation led to decreased affinity. This corresponds with the observation that the carboxylic group mediates binding to the integrin pocket divalent cations at the metal-ion-dependent adhesion (MIDAS) motif site. A similar reduced affinity was documented for deaminated forms of T3 (triac) and T4 (tetrac). Lastly, the reverse forms of T3, T3S, and T3AM showed higher Amber scores relative to their native form, indicating that iodination at position 5 is associated with increased binding affinity compared to position 5'.
Three-dimensional docking of various TH metabolites uncovered a structural basis for a differential computational free energy to the αvβ3 integrin. These findings may suggest that naturally occurring endogenous TH metabolites may impact integrin-mediate intracellular pathways in physiology and cancer.
甲状腺激素（TH），T4 和 T3，通过与膜受体 αvβ3 整联蛋白结合来介导促有丝分裂作用。脱氨类似物 tetrac 能有效阻止 TH 与该受体结合，从而阻止其作用。虽然已经发表了关于 TH 与 αvβ3 整联蛋白结合的计算数据，但缺乏对其他 TH 代谢物的综合分析。
使用 DOCK6 对 26 种 TH 代谢物（包括生物活性甲状腺激素 T3 和 T4 以及一系列硫酸化、脱碘、脱氨或脱羧代谢物）进行对接，基于整合素晶体结构的三维表示。由于整合素上的 TH 结合位点与明确定义的 RGD 结合位点非常接近，因此还包括线性和环状 RGD 作为参考。使用网格得分和 Amber 得分以及距离可移动区域协议为每个受体-配体复合物计算结合能。
所有 TH 分子均表现出负自由能，表明与 αvβ3 整联蛋白具有亲和力。值得注意的是，基于网格和 Amber 得分，与环状 RGD 和一系列检查的 TH 代谢物相比，3,3' T2（3,3' T2S）和 T4（T4S）的硫酸化形式对整合素表现出最高的结合亲和力。主要的甲状腺激素 T3 和 T4 对整合素具有高亲和力，优于线性 RGD。对于所有激素代谢物，脱羧作用导致亲和力降低。这与羧酸基团介导与整合素口袋结合的观察结果一致，二价阳离子在金属离子依赖性粘附（MIDAS）基序位点。类似的亲和力降低也记录在 T3（三碘乙酸）和 T4（tetrac）的脱氨形式中。最后，T3、T3S 和 T3AM 的反向形式相对于其天然形式表现出更高的 Amber 得分，表明 5 位碘取代与 5'位相比具有更高的结合亲和力。
各种 TH 代谢物的三维对接揭示了与 αvβ3 整联蛋白的差异计算自由能的结构基础。这些发现可能表明，天然存在的内源性 TH 代谢物可能会影响生理和癌症中整合素介导的细胞内途径。
