Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands.
Human DP and EP2 prostanoid receptors take on distinct forms depending on the diverse binding of different ligands.
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人类 DP 和 EP2 前列腺素受体根据不同配体的不同结合而呈现不同的形式。
DOI：
10.1111/febs.13899
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Murayama T.
中科院分区：
文献类型：
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作者：
Suganami A;Fujino H;Okura I;Yanagisawa N;Sugiyama H;Regan JW;Tamura Y;Murayama T.
人D型前列腺素（DP）和E型前列腺素2（EP 2）受体是G蛋白偶联受体，被认为是前列腺素受体中最密切相关的受体，因为它们是通过串联复制产生的。DP受体同源配体前列腺素D2（PGD 2）不仅能激活DP受体，还能激活EP 2受体。同样，EP 2受体同源配体前列腺素E2（PGE 2）除了EP受体外，还具有激活DP受体的能力，以刺激cAMP形成。然而，由于PGD 2和/或PGE 2激活DP和EP 2受体至相似的最大水平，即它们相似的功效，除了它们不同的亲和力之外，还没有详细确定每种受体中配体之间的差异。在本文中，我们使用计算机模拟来预测DP或EP 2受体与作为参比前列腺素的PGD 2、PGE 2或前列腺素F2α之间的结合模式，证明DP和EP 2受体可能会根据不同配体的不同结合而呈现不同的形式。由于这些配体具有使这些受体形成具有离散信号传导途径的不同构象的潜力，因此它们被认为是内源性偏性配体。此外，通过使用功能测定，DP受体对非同源配体的亲和性比EP 2受体的亲和性低约10倍。因此，EP 2受体似乎能够比DP受体更好地区分内源性配体，从而两种受体作为复制基因的拷贝，可以获得相对于彼此的角色共享功能。
Human D‐type prostanoid (DP) and E‐type prostanoid 2 (EP2) receptors are G protein‐coupled receptors and are regarded as the most closely related receptors among prostanoid receptors because they are generated by tandem duplication. The DP receptor‐cognate ligand, prostaglandin D2(PGD2) has the ability to activate not only DP receptors but also EP2 receptors. Likewise, the EP2 receptor‐cognate ligand, prostaglandin E2(PGE2) has the ability to activate DP receptors in addition to EP receptors in order to stimulate cAMP formation. However, since PGD2and/or PGE2activate DP and EP2 receptors to similar maximal levels, that is, their similar efficacies, differences between the ligands in each receptor have not yet been determined in detail except for their different affinities. Herein we demonstrated, using anin silicosimulation to predict binding patterns among DP or EP2 receptors and PGD2, PGE2, or prostaglandin F2αas the reference prostanoid, that DP and EP2 receptors plausibly take on distinct forms depending on the diverse binding of different ligands. Since these ligands have the potential to make these receptors form distinct conformations with discrete signaling pathways, they are consequently regarded as endogenous biased ligands. Moreover, by using functional assays, the susceptibilities of the DP receptors to the noncognate ligands were approximately 10 times lower than those of EP2 receptors. Thus, EP2 receptors seem to be able to distinguish endogenous ligands better than DP receptors, thereby both receptors are plausibly gaining role‐sharing functions with respect to one another as the copies of duplicated gene.