丹麦奥尔胡斯大学Poul Nissen、瑞士罗氏制药Roger J. P. Dawson及德国欧洲分子生物学实验室Thomas R. Schneider课题组，合作揭示了抑制甘氨酸再摄取的结构机制。该项研究成果在线发表在2021年3月3日的《自然》上。

使用合成的单结构域抗体（sybody）和串联同步加速器晶体学，研究人员解析了与苯甲酰基哌嗪化学抑制剂结合的人甘氨酸转运蛋白1（GlyT1）结构，其分辨率为3.4  Å。研究发现该抑制剂将GlyT1锁定在向内开放构象，并与释放途径的细胞内门结合，其与甘氨酸释放位点重叠。该抑制剂可能通过质膜细胞质小叶结合GlyT1。

该研究揭示的抑制机制使得合理设计新的、临床有效GlyT1抑制剂成为可能。

据了解，GlyT1通过钠和氯依赖的甘氨酸再摄取机制来调节甘氨酸介导的神经元兴奋和抑制。抑制GlyT1延长了神经递质的信号传导，长期以来一直作为研发针对多种中枢神经系统疾病（包括精神分裂症和认知障碍）治疗的关键靶标。

附：英文原文

Title: Structural insights into the inhibition of glycine reuptake

Author: Azadeh Shahsavar, Peter Stohler, Gleb Bourenkov, Iwan Zimmermann, Martin Siegrist, Wolfgang Guba, Emmanuel Pinard, Steffen Sinning, Markus A. Seeger, Thomas R. Schneider, Roger J. P. Dawson, Poul Nissen

Issue&Volume: 2021-03-03

Abstract: The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine1,2,3. Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments4. Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors.

DOI: 10.1038/s41586-021-03274-z

Source: https://www.nature.com/articles/s41586-021-03274-z