PDF(Pubmed)
Abstract：
The sigma-1 receptor (σ1R) is a non-opioid membrane receptor, which responds to a diverse array of synthetic ligands to exert various pharmacological effects. Meanwhile, candidates for endogenous ligands of σ1R have also been identified. However, how endogenous ligands bind to σ1R remains unknown. Here, we present crystal structures of σ1R from Xenopus laevis (xlσ1R) bound to two endogenous neurosteroid ligands, progesterone (a putative antagonist) and dehydroepiandrosterone sulfate (DHEAS) (a putative agonist), at 2.15-3.09 Å resolutions. Both neurosteroids bind to a similar location in xlσ1R mainly through hydrophobic interactions, but surprisingly, with opposite binding orientations. DHEAS also forms hydrogen bonds with xlσ1R, whereas progesterone interacts indirectly with the receptor through water molecules near the binding site. Binding analyses are consistent with the xlσ1R-neurosteroid complex structures. Furthermore, molecular dynamics simulations and structural data reveal a potential water entry pathway. Our results provide insight into binding of two endogenous neurosteroid ligands to σ1R.
摘要：
sigma-1受体（σ1R）是一种非阿片膜受体，它响应各种合成配体以发挥各种药理作用。同时,还确定了σ1R内源性配体的候选物。然而,内源性配体如何与σ1R结合仍然未知。这里,我们提出了与两个内源性神经类固醇配体结合的来自非洲爪的σ1R（xlσ1R）的晶体结构，孕酮（推定的拮抗剂）和硫酸脱氢表雄酮（DHEAS）（推定的激动剂），分辨率为2.15-3.09。两种神经类固醇主要通过疏水相互作用结合到xlσ1R中的相似位置，但令人惊讶的是，具有相反的绑定方向。DHEAS还与xlσ1R形成氢键，而孕酮通过结合位点附近的水分子与受体间接相互作用。结合分析与xlσ1R-神经类固醇复合物结构一致。此外，分子动力学模拟和结构数据揭示了潜在的水进入途径。我们的结果为两个内源性神经类固醇配体与σ1R的结合提供了见解。
