摘要: The norepinephrine transporter (NET) plays a pivotal role in regulating neurotransmitter balance and is critical for normal physiology and neurobiology. Dysfunction of NET has been implicated in numerous neuropsychiatric diseases including depression, anxiety, attention deficit hyperactivity disorder, and Parkinson’s disease. Here we report cryo-EM structures of NET in apo and substrate-bound forms, as well as complexes with six antidepressants. The structures reveal an unexpected NET dimer interface predominantly mediated by cholesterol and lipid molecules. The substrate norepinephrine is found to bind deep within the central binding pocket, with its amine group interacting with a conserved aspartate. The structures also provide insight into antidepressant recognition, including how subtle differences in binding poses confer selectivity over other monoamine transporters. Together these breakthrough findings significantly advance our understanding of NET regulation and inhibition, providing templates for designing improved antidepressants to treat neuropsychiatric disorders.
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来自:
张衡
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期刊:
施普林格·自然
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分类:
药物科学
>>
结构生物学
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投稿状态:
已被期刊接收
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引用:
ChinaXiv:202404.00367
(或此版本
ChinaXiv:202404.00367V1)
DOI:10.12074/202404.00367V1
CSTR:32003.36.ChinaXiv.202404.00367.V1
- 推荐引用方式:
Heng Zhang,Yuling Yin,Tianwei Zhang,Canrong Wu,Wen Hu,Xinheng He,Benxun Pan,Sanshan Jin,Qingning Yuan,H. Eric Xu,Yi Jiang.(2024).Decoding homodimerization and antidepressant recognition at the norepinephrine transporter.施普林格·自然.doi:10.12074/202404.00367V1
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