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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The second extracellular loop of the dopamine D_2 receptor lines the binding-site crevice
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The second extracellular loop of the dopamine D_2 receptor lines the binding-site crevice

机译：多巴胺D_2受体的第二个细胞外环位于结合位点缝隙中

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摘要

The binding site of the dopamine D_2 receptor (D2R), like those of homologous rhodopsin-like G protein-coupled receptors (GPCRs) that bind small molecules, is contained within a water-accessible crevice formed among its seven transmembrane segments (TMs). The high-resolution structure of bovine rhodopsin, however, revealed that the second extracellular loop (E2), which connects TM4 and TM5, folds down into the transmembrana domain and forms part of the ligand-binding surface for retinal. Whether E2 plays a related role in other rhodopsin-like GPCRs is unclear. To address this issue, we have now mutated to cysteine, one at a time, 10 consecutive residues in E2 of D2R. The reaction of five of these mutants with sulfhydryl reagents inhibited antagonist binding, and bound antagonist protected two, I184C and N186C, from reaction. The pattern of accessibility in E2 is consistent with a structure similar to that of bovine rhodopsin, in which the region C-terminal to the conserved disulf ide bond is deeper in the binding-site crevice than is the N-terminal part of E2. Thus, E2 likely contributes to the binding site in the D2R and probably in other aminergic GPCRs as well. Knowledge of its detailed positioning and interactions with ligand would benefit GPCR molecular modeling and facilitate the design of novel drugs.
机译：多巴胺D_2受体（D2R）的结合位点类似于结合小分子的同源视紫红质样G蛋白偶联受体（GPCR）的结合位点，包含在其七个跨膜片段（TM）之间形成的可水接触缝隙中。牛视紫红质的高分辨率结构显示，连接TM4和TM5的第二个细胞外环（E2）向下折叠成跨膜结构域，并形成视网膜的配体结合表面的一部分。 E2是否在其他视紫红质样GPCR中起相关作用尚不清楚。为了解决这个问题，我们现在将D2R的E2中的10个连续残基一次突变为半胱氨酸。这些突变体中的五个与巯基试剂的反应抑制了拮抗剂的结合，结合的拮抗剂保护了两个I184C和N186C免受反应。 E2中可及性的模式与类似于牛视紫红质的结构一致，其中保守的二硫键的C端区域在结合位点缝隙中比E2的N端部分深。因此，E2可能有助于D2R和其他胺能GPCR中的结合位点。对其详细定位和与配体的相互作用的了解将有益于GPCR分子建模并促进新药的设计。

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