A lower X-gate in TASK channels traps inhibitors within the vestibule

doi:10.1038/s41586-020-2250-8

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2250-8
	A lower X-gate in TASK channels traps inhibitors within the vestibule
	Chen, Tao 1,2,3; Nomura, Kinya 1; Wang, Xiaolin 4; Sohrabi, Reza 1,5; Xu, Jin 6; Yao, Lingya 4; Paasch, Bradley C.1; Ma, Li 1; Kremer, James 1; Cheng, Yuti 1,3; Zhang, Li 1,3; Wang, Nian 6; Wang, Ertao 4; Xin, Xiu-Fang 4,7; He, Sheng Yang 1,3,5
	2020-04-01
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
文章类型	Article;Early Access
语种	英语
国家	England; Germany; Peoples R China
英文关键词	TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an ' X-gate' -created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders. The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000529600400012
WOS关键词	DOMAIN K+ CHANNEL ; SEQUENCE ALIGNMENT EDITOR ; POTASSIUM CHANNELS ; CRYSTAL-STRUCTURE ; PH ; ANESTHETICS ; DETERMINANTS ; EXPRESSION ; MECHANISM ; VOLATILE
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281400
专题	地球科学资源环境科学气候变化
作者单位	1.Michigan State Univ, Dept Energy Plant Res Lab, E Lansing, MI 48824 USA; 2.Huazhong Agr Univ, State Key Lab Agr Microbiol, Wuhan, Peoples R China; 3.Michigan State Univ, Howard Hughes Med Inst, E Lansing, MI 48824 USA; 4.Chinese Acad Sci, Inst Plant Physiol & Ecol, CAS Ctr Excellence Mol Plant Sci, Natl Key Lab Plant Mol Genet, Shanghai, Peoples R China; 5.Michigan State Univ, Plant Resilience Inst, E Lansing, MI 48824 USA; 6.Univ Florida, Inst Food & Agr Sci, Dept Microbiol & Cell Sci, Citrus Res & Educ Ctr, Lake Alfred, FL USA; 7.Chinese Acad Sci, Inst Plant Physiol & Ecol, CAS JIC Ctr Excellence Plant & Microbial Sci CEPA, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Chen, Tao,Nomura, Kinya,Wang, Xiaolin,et al. A lower X-gate in TASK channels traps inhibitors within the vestibule[J]. NATURE,2020.
APA	Chen, Tao.,Nomura, Kinya.,Wang, Xiaolin.,Sohrabi, Reza.,Xu, Jin.,...&He, Sheng Yang.(2020).A lower X-gate in TASK channels traps inhibitors within the vestibule.NATURE.
MLA	Chen, Tao,et al."A lower X-gate in TASK channels traps inhibitors within the vestibule".NATURE (2020).