Structural basis of ketamine action on human NMDA receptors

doi:10.1038/s41586-021-03769-9

	Structural basis of ketamine action on human NMDA receptors
	Zhang, Youyi 1,2; Ye, Fei 3; Zhang, Tongtong 1,2; Lv, Shiyun 1,2; Zhou, Liping 2,4; Du, Daohai 4; Lin, He 5; Guo, Fei ; Luo, Cheng 2,4; Zhu, Shujia 1,2,6
刊名	NATURE
	2021-08-12
卷号	596 期号:7871 页码:301-+
ISSN号	0028-0836
DOI	10.1038/s41586-021-03769-9
通讯作者	Luo, Cheng(cluo@simm.ac.cn) ; Zhu, Shujia(shujiazhu@ion.ac.cn)
英文摘要	Ketamine is a non-competitive channel blocker of N-methyl-d-aspartate (NMDA) receptors(1). A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants(2,3). Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant(4). Here we describe the cryo-electron microscope structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids-leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1-were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.
资助项目	National Natural Science Foundation of China[31771115] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81821005] ; National Key R&D Program of China[2017YFA0505700] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB32020000] ; Shanghai Municipal Science and Technology Major Project[2018SHZDZX05] ; Thousand Young Talents Program ; Shanghai Municipal Health Commission in China[18431907100] ; Shanghai Municipal Health Commission in China[19XD1404700]
WOS关键词	SYNAPTIC PLASTICITY ; ANTIDEPRESSANT ; INHIBITION ; DEPRESSION ; MECHANISM ; BLOCKADE
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATURE PORTFOLIO
WOS记录号	WOS:000678535100010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298262]
专题	中国科学院上海药物研究所
通讯作者	Luo, Cheng; Zhu, Shujia
作者单位	1.Chinese Acad Sci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Inst Neurosci, State Key Lab Neurosci, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Ctr Chem Biol,Drug Discovery & Design Ctr, Shanghai, Peoples R China 5.Third Res Inst Minist Publ Secur, Criminal Invest Technol Dept, Shanghai, Peoples R China 6.Shanghai Ctr Brain Sci & Brain Inspired Intellige, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Youyi,Ye, Fei,Zhang, Tongtong,et al. Structural basis of ketamine action on human NMDA receptors[J]. NATURE,2021,596(7871):301-+.
APA	Zhang, Youyi.,Ye, Fei.,Zhang, Tongtong.,Lv, Shiyun.,Zhou, Liping.,...&Zhu, Shujia.(2021).Structural basis of ketamine action on human NMDA receptors.NATURE,596(7871),301-+.
MLA	Zhang, Youyi,et al."Structural basis of ketamine action on human NMDA receptors".NATURE 596.7871(2021):301-+.