High resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxine
High resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxine
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DOI：
10.1074/jbc.m313553200
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发表时间：
2004-06-18
影响因子：
4.8
通讯作者：
Sauer-Eriksson, AE
中科院分区：
文献类型：
--
作者：
Eneqvist, T;Lundberg, E;Sauer-Eriksson, AE
甲状腺素运载蛋白（TTR）是一种细胞外转运蛋白，参与甲状腺激素和维生素A的分布。迄今为止，TTR仅在脊椎动物中发现，其中鱼类TTR与人类TTR的同源性最低（47%）。人和鱼TTR结合甲状腺激素3，5，3 '-三碘-L-甲状腺原氨酸（T-3）和3，5，3'，5 '-四碘-L-甲状腺原氨酸（甲状腺素，T-4）。人TTR对T-4的亲和力高于对T-3的亲和力，而对鱼TTR的亲和力则相反。已确定Sparus aurata（海鲷）TTR的X射线结构为1.75埃分辨率的脱辅基蛋白，并与1.9埃分辨率的配体T-3和T-4结合。载脂蛋白结构与人TTR相似，仅在β链D处发生结构变化。该链形成类似于鸡TTR中的延伸环构象。鱼TTR·T-4复合物显示T-4结合位点与人TTR相似但不相同，而TTR·T-3复合物显示I3'卤素位于通常由T-4的羟基占据的位点。的显着更广泛的入口结合通道在海鲷TTR，结合其较窄的腔，提供了一个结构上的解释不同的结合亲和力的人和鱼TTR的T-3和T-4。
Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3'-triiodo-L-thyronine (T-3) and 3,5,3', 5'-tetraiodo-L-thyronine (thyroxine, T-4). Human TTR has higher affinity for T-4 than T-3, whereas the reverse holds for piscine TTR. X-ray structures of Sparus aurata (sea bream) TTR have been determined as the apo-protein at 1.75 Angstrom resolution and bound to ligands T-3 and T-4, both at 1.9 Angstrom resolution. The apo structure is similar to human TTR with structural changes only at beta-strand D. This strand forms an extended loop conformation similar to the one in chicken TTR. The piscine TTR.T-4 complex shows the T-4-binding site to be similar but not identical to human TTR, whereas the TTR.T-3 complex shows the I3' halogen situated at the site normally occupied by the hydroxyl group of T-4. The significantly wider entrance of the hormone-binding channel in sea bream TTR, in combination with its narrower cavity, provides a structural explanation for the different binding affinities of human and piscine TTR to T-3 and T-4.