Structural Insights into the Atomistic Mechanisms of Uric Acid Recognition and Translocation of Human Urate Anion Transporter 1.
Structural Insights into the Atomistic Mechanisms of Uric Acid Recognition and Translocation of Human Urate Anion Transporter 1.
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尿酸识别和人尿酸盐阴离子转运蛋白易位的原子机制的结构见解 1
DOI：
10.1021/acsomega.0c05360
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发表时间：
2020-12-29
期刊：
影响因子：
4.1
通讯作者：
Pang J
中科院分区：
文献类型：
--
作者：
Zhao Z;Jiang Y;Li L;Chen Y;Li Y;Lan Q;Wu T;Lin C;Cao Y;Nandakumar KS;Zhou P;Tian Y;Pang J
背景：人尿酸转运蛋白1(HURAT1)是治疗高尿酸血症最关键的治疗靶点。然而，由于缺乏结构细节，尿酸与URAT1之间的分子相互作用仍不清楚。方法：在本研究中，采用多种方法(同源性建模、序列比对、对接和突变)来解释尿酸转运的原子学机制。结果：hURAT1中TMD7中的W357-F365残基和TMD11中的P484-R487残基在与尿酸结合和引起随后的结构变化方面具有独特的作用。这些位于运输通道中的残基被发现与结构变化有关，Vmax值降低而蛋白质水平没有变化。此外，W357、G361、T363、F365和R487残基可能具有与尿酸结合的高亲和力。HURAT1的外向开放同源模型揭示了这两个结构域在hURAT1构象变化中的关键作用。TMD5中的F241和H245，TMD11中的R477和R487可能与尿酸有较高的亲和力，对接分析表明，它们也可能增强对抑制剂的亲和力。突变体的Vmax和正电荷对尿酸选择性的贡献证明了R477与结构变化的关系。结论：TMD7中的W357-F365、TMD11中的P484-R487以及残基F241、H245和R477对尿酸的转运和识别起关键作用。
Background: Human urate transporter 1 (hURAT1) is the most pivotal therapeutic target for treating hyperuricemia. However, the molecular interactions between uric acid and URAT1 are still unknown due to lack of structural details. Methods: In the present study, several methods (homology modeling, sequence alignment, docking, and mutagenesis) were used to explain the atomistic mechanisms of uric acid transport of hURAT1. Results: Residues W357-F365 in the TMD7 and P484-R487 in the TMD11 present in the hURAT1 have unique roles in both binding to the uric acid and causing subsequent structural changes. These residues, located in the transport tunnel, were found to be related to the structural changes, as demonstrated by the reduced Vmax values and an unaltered expression of protein level. In addition, W357, G361, T363, F365, and R487 residues may confer high affinity for binding to uric acid. An outward-open homology model of hURAT1 revealed a crucial role for these two domains in the conformational changes of hURAT1. F241 and H245 in TMD5, and R477 and R487 in TMD11 may confer high affinity for uric acid, and as the docking analysis suggests, they may also enhance the affinity for the inhibitors. R477 relation to the structural changes was demonstrated by the Vmax values of the mutants and the contribution of positive charge to the uric acid selectivity. Conclusions: W357-F365 in TMD7, P484-R487 in TMD11, and residues F241, H245, and R477 were found to be critical for the translocation and recognition of uric acid.
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影响因子：
14.9
作者：
Dobson L;Reményi I;Tusnády GE
通讯作者：
Tusnády GE
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
3.6
作者：
Gorboulev, V;Shatskaya, N;Koepsell, H
通讯作者：
Koepsell, H
影响因子：
4.8
作者：
Egenberger, Brigitte;Gorboulev, Valentin;Koepsell, Hermann
通讯作者：
Koepsell, Hermann
影响因子：
2.9
作者：
Feng, B;Dresser, MJ;Giacomini, KM
通讯作者：
Giacomini, KM