From small sweeteners to sweet proteins: Anatomy of the binding sites of the human T1R2_T1R3 receptor
From small sweeteners to sweet proteins: Anatomy of the binding sites of the human T1R2_T1R3 receptor
复制标题
DOI：
10.1021/jm0503345
复制
发表时间：
2005-08-25
影响因子：
7.3
通讯作者：
Temussi, PA
中科院分区：
文献类型：
--
作者：
Morini, G;Bassoli, A;Temussi, PA
甜味受体是由T1R2和T1R3亚基形成的异二聚体G蛋白偶联受体（GPCR）蛋白，识别几种甜味化合物，包括碳水化合物、氨基酸、肽、蛋白质和合成甜味剂。它与代谢型谷氨酸mGluR1受体的相似性使我们能够建立同源模型。以mGluR 1模板的胞外配体结合结构域的A（闭合）或B（开放）链为模型，由人T1 R2和T1 R3亚基的组合形成的所有可能的二聚体产生低分子量甜味剂的四个配体结合位点。通过对接一组代表所有类别的甜味化合物的分子并计算配体结合的自由能来探测这些位点。这些位点不容易接近甜蛋白，但计算机对接实验表明，甜蛋白可以结合到第二个位点，而不进入深裂。我们的模型解释了许多关于甜味剂味道的实验观察，包括甜味协同作用，并可以帮助设计新的甜味剂。
The sweet taste receptor, a heterodimeric G protein coupled receptor (GPCR) protein, formed by the T1R2 and T1R3 subunits, recognizes several sweet compounds including carbohydrates, amino acids, peptides, proteins, and synthetic sweeteners. Its similarity with the metabotropic glutamate mGluR1 receptor allowed us to build homology models. All possible dimers formed by combinations of the human T1R2 and T1R3 subunits, modeled on the A (closed) or B (open) chains of the extracellular ligand binding domain of the mGluR1 template, yield four ligand binding sites for low-molecular-weight sweeteners. These sites were probed by docking a set of molecules representative of all classes of sweet compounds and calculating the free energy of ligand binding. These sites are not easily accessible to sweet proteins, but docking experiments in silico showed that sweet proteins can bind to a secondary site without entering the deep cleft. Our models account for many experimental observations on the tastes of sweeteners, including sweetness synergy, and can help to design new sweeteners.