中国医学科学院北京协和医学院吴惊香研究团队报道了去甲肾上腺素转运体的底物结合及抑制机制。该项研究成果发表在2024年8月14日出版的《自然》上。

该研究团队提供了人类甲肾上腺素转运蛋白 (hNET)在三种功能状态下的低温电子显微镜结构-载子状态，以及与底物间碘苄基胍(MIBG)或正位抑制剂radafaxine结合的状态。

这些结构被捕获为面向内的构象，具有紧密密封的细胞外门和开放的细胞内门。底物MIBG结合在hNET的中心。Radafaxine也占据底物结合位点，可能阻断hNET的结构转变，从而起到抑制作用。这些结构提供了对底物识别和hNET正构抑制机制的见解。

据了解，去甲肾上腺素转运蛋白（NET，由SLC6A2编码)将释放的大部分去甲肾上腺素重新摄取回突触前末端，从而影响突触的去甲肾上腺素水平。基因突变和NET失调与人类一系列神经系统疾病有关，使NET成为一个重要的治疗靶点。然而，NET的结构和机制尚不清楚。

附：英文原文

Title: Substrate binding and inhibition mechanism of norepinephrine transporter

Author: Ji, Wenming, Miao, Anran, Liang, Kai, Liu, Jiameng, Qi, Yuhan, Zhou, Yue, Duan, Xinli, Sun, Jixue, Lai, Lipeng, Wu, Jing-Xiang

Issue&Volume: 2024-08-14

Abstract: Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states—the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

DOI: 10.1038/s41586-024-07810-5

Source: https://www.nature.com/articles/s41586-024-07810-5