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A lower X-gate in TASK channels traps inhibitors within the vestibule 期刊论文
NATURE, 2020
作者:  Chen, Tao;  Nomura, Kinya;  Wang, Xiaolin;  Sohrabi, Reza;  Xu, Jin;  Yao, Lingya;  Paasch, Bradley C.;  Ma, Li;  Kremer, James;  Cheng, Yuti;  Zhang, Li;  Wang, Nian;  Wang, Ertao;  Xin, Xiu-Fang;  He, Sheng Yang
收藏  |  浏览/下载:37/0  |  提交时间:2020/07/03

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.


  
Multi-criteria analysis of policies for implementing clean energy vehicles in China 期刊论文
ENERGY POLICY, 2019, 129: 826-840
作者:  Li, Chengjiang;  Negnevitsky, Michael;  Wang, Xiaolin;  Yue, Wen Long;  Zou, Xin
收藏  |  浏览/下载:10/0  |  提交时间:2019/11/26
Clean energy vehicles  Multi-criteria analysis  Analytic hierarchy process  VIKOR  
Fifteen-year statistical analysis of cloud characteristics over China using Terra and Aqua Moderate Resolution Imaging Spectroradiometer observations 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2019, 39 (5) : 2612-2629
作者:  Zhao, Chuanfeng;  Chen, Yuyang;  Li, Jiming;  Letu, Husi;  Su, Yunfei;  Chen, Tianmeng;  Wu, Xiaolin
收藏  |  浏览/下载:17/0  |  提交时间:2019/11/26
China  cloud effective radius  cloud fraction  cloud optical thickness  cloud top pressure  MODIS  
An autoimmune disease variant of IgG1 modulates B cell activation and differentiation 期刊论文
SCIENCE, 2018, 362 (6415) : 700-+
作者:  Chen, Xiangjun;  Sun, Xiaolin;  Yang, Wei;  Yang, Bing;  Zhao, Xiaozhen;  Chen, Shuting;  He, Lili;  Chen, Hui;  Yang, Changmei;  Xiao, Le;  Chang, Zai;  Guo, Jianping;  He, Jing;  Zhang, Fuping;  Zheng, Fang;  Hu, Zhibin;  Yang, Zhiyong;  Lou, Jizhong;  Zheng, Wenjie;  Qi, Hai;  Xu, Chenqi;  Zhang, Hong;  Shan, Hongying;  Zhou, Xu-jie;  Wang, Qingwen;  Shi, Yi;  Lai, Luhua;  Li, Zhanguo;  Liu, Wanli
收藏  |  浏览/下载:15/0  |  提交时间:2019/11/27
Five-S-isotope evidence of two distinct mass-independent sulfur isotope effects and implications for the modern and Archean atmospheres 期刊论文
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (34) : 8541-8546
作者:  Lin, Mang;  Zhang, Xiaolin;  Li, Menghan;  Xu, Yilun;  Zhang, Zhisheng;  Tao, Jun;  Su, Binbin;  Liu, Lanzhong;  Shen, Yanan;  Thiemens, Mark H.
收藏  |  浏览/下载:9/0  |  提交时间:2019/11/27
cosmogenic sulfur-35  stable sulfur isotope anomalies  sulfate aerosols  combustion  recombination reactions  
Investigation of Turbulent Entrainment-Mixing Processes With a New Particle-Resolved Direct Numerical Simulation Model 期刊论文
JOURNAL OF GEOPHYSICAL RESEARCH-ATMOSPHERES, 2018, 123 (4) : 2194-2214
作者:  Gao, Zheng;  Liu, Yangang;  Li, Xiaolin;  Lu, Chunsong
收藏  |  浏览/下载:4/0  |  提交时间:2019/04/09
Egg accumulation with 3D embryos provides insight into the life history of a pterosaur 期刊论文
SCIENCE, 2017, 358 (6367) : 1197-1201
作者:  Wang, Xiaolin;  Kellner, Alexander W. A.;  Jiang, Shunxing;  Cheng, Xin;  Wang, Qiang;  Ma, Yingxia;  Paidoula, Yahefujiang;  Rodrigues, Taissa;  Chen, He;  Sayao, Juliana M.;  Li, Ning;  Zhang, Jialiang;  Bantim, Renan A. M.;  Meng, Xi;  Zhang, Xinjun;  Qiu, Rui;  Zhou, Zhonghe
收藏  |  浏览/下载:13/0  |  提交时间:2019/11/27
Weak Thermocline Mixing in the North Pacific Low-Latitude Western Boundary Current System 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2017, 44 (20)
作者:  Liu, Zhiyu;  Lian, Qiang;  Zhang, Fangtao;  Wang, Lei;  Li, Mingming;  Bai, Xiaolin;  Wang, Jianing;  Wang, Fan
收藏  |  浏览/下载:9/0  |  提交时间:2019/04/09
Redox chemistry changes in the Panthalassic Ocean linked to the end-Permian mass extinction and delayed Early Triassic biotic recovery 期刊论文
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (8) : 1806-1810
作者:  Zhang, Guijie;  Zhang, Xiaolin;  Hu, Dongping;  Li, Dandan;  Algeo, Thomas J.;  Farquhar, James;  Henderson, Charles M.;  Qin, Liping;  Shen, Megan;  Shen, Danielle;  Schoepfer, Shane D.;  Chen, Kefan;  Shen, Yanan
收藏  |  浏览/下载:16/0  |  提交时间:2019/11/27
end-Permian mass extinction  Panthalassic Ocean  multiple sulfur  isotopes  sulfidic waters