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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:36/0  |  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.


  
Nanoplasma-enabled picosecond switches for ultrafast electronics (vol 579, pg 534, 2020) 期刊论文
NATURE, 2020, 580 (7803) : E8-E8
作者:  Li, Jing;  Xu, Chuanliang;  Lee, Hyung Joo;  Ren, Shancheng;  Zi, Xiaoyuan;  Zhang, Zhiming;  Wang, Haifeng;  Yu, Yongwei;  Yang, Chenghua;  Gao, Xiaofeng;  Hou, Jianguo;  Wang, Linhui;  Yang, Bo;  Yang, Qing;  Ye, Huamao;  Zhou, Tie;  Lu, Xin;  Wang, Yan;  Qu, Min;  Yang, Qingsong;  Zhang, Wenhui;  Shah, Nakul M.;  Pehrsson, Erica C.;  Wang, Shuo;  Wang, Zengjun;  Jiang, Jun;  Zhu, Yan;  Chen, Rui;  Chen, Huan;  Zhu, Feng;  Lian, Bijun;  Li, Xiaoyun;  Zhang, Yun;  Wang, Chao;  Wang, Yue;  Xiao, Guangan;  Jiang, Junfeng;  Yang, Yue;  Liang, Chaozhao;  Hou, Jianquan;  Han, Conghui;  Chen, Ming;  Jiang, Ning;  Zhang, Dahong;  Wu, Song;  Yang, Jinjian;  Wang, Tao;  Chen, Yongliang;  Cai, Jiantong;  Yang, Wenzeng;  Xu, Jun;  Wang, Shaogang;  Gao, Xu;  Wang, Ting;  Sun, Yinghao
收藏  |  浏览/下载:25/0  |  提交时间:2020/07/03
Mott and generalized Wigner crystal states in WSe2/WS2 moire superlattices 期刊论文
NATURE, 2020, 579 (7799) : 359-+
作者:  Yuan, Jie;  Chang, Si-Yuan;  Yin, Shi-Gang;  Liu, Zhi-Yang;  Cheng, Xiu;  Liu, Xi-Juan;  Jiang, Qiang;  Gao, Ge;  Lin, De-Ying;  Kang, Xin-Lei;  Ye, Shi-Wei;  Chen, Zheng;  Yin, Jiang-An;  Hao, Pei;  Jiang, Lubin;  Cai, Shi-Qing
收藏  |  浏览/下载:50/0  |  提交时间:2020/07/03

Strongly correlated insulating Mott and generalized Wigner phases are detected in WSe2/WS2 moire superlattices, and their electrical properties and excited spin states are studied using an optical technique.


Moire superlattices can be used to engineer strongly correlated electronic states in two-dimensional van der Waals heterostructures, as recently demonstrated in the correlated insulating and superconducting states observed in magic-angle twisted-bilayer graphene and ABC trilayer graphene/boron nitride moire superlattices(1-4). Transition metal dichalcogenide moire heterostructures provide another model system for the study of correlated quantum phenomena(5) because of their strong light-matter interactions and large spin-orbit coupling. However, experimental observation of correlated insulating states in this system is challenging with traditional transport techniques. Here we report the optical detection of strongly correlated phases in semiconducting WSe2/WS2 moire superlattices. We use a sensitive optical detection technique and reveal a Mott insulator state at one hole per superlattice site and surprising insulating phases at 1/3 and 2/3 filling of the superlattice, which we assign to generalized Wigner crystallization on the underlying lattice(6-11). Furthermore, the spin-valley optical selection rules(12-14) of transition metal dichalcogenide heterostructures allow us to optically create and investigate low-energy excited spin states in the Mott insulator. We measure a very long spin relaxation lifetime of many microseconds in the Mott insulating state, orders of magnitude longer than that of charge excitations. Our studies highlight the value of using moire superlattices beyond graphene to explore correlated physics.


  
Mutational signature in colorectal cancer caused by genotoxic pks(+)E. coli 期刊论文
NATURE, 2020, 580 (7802) : 269-+
作者:  Lin, Xi;  Li, Mingyue;  Wang, Niandong;  Wu, Yiran;  Luo, Zhipu;  Guo, Shimeng;  Han, Gye-Won;  Li, Shaobai;  Yue, Yang;  Wei, Xiaohu;  Xie, Xin;  Chen, Yong;  Zhao, Suwen;  Wu, Jian;  Lei, Ming;  Xu, Fei
收藏  |  浏览/下载:23/0  |  提交时间:2020/07/03

Various species of the intestinal microbiota have been associated with the development of colorectal cancer(1,2), but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin(3). This compound is believed to alkylate DNA on adenine residues(4,5) and induces double-strand breaks in cultured cells(3). Here we expose human intestinal organoids to genotoxic pks(+)E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.


Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks(+) island develop a distinct mutational signature associated with colorectal cancer.


  
Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells 期刊论文
NATURE, 2020, 577 (7792) : 676-+
作者:  Zhao, Ruozhu;  Chen, Xin;  Ma, Weiwei;  Zhang, Jinyu;  Guo, Jie;  Zhong, Xiu;  Yao, Jiacheng;  Sun, Jiahui;  Rubinfien, Julian;  Zhou, Xuyu;  Wang, Jianbin;  Qi, Hai
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

Empirical and anecdotal evidence has associated stress with accelerated hair greying (formation of unpigmented hairs)(1,2), but so far there has been little scientific validation of this link. Here we report that, in mice, acute stress leads to hair greying through the fast depletion of melanocyte stem cells. Using a combination of adrenalectomy, denervation, chemogenetics(3,4), cell ablation and knockout of the adrenergic receptor specifically in melanocyte stem cells, we find that the stress-induced loss of melanocyte stem cells is independent of immune attack or adrenal stress hormones. Instead, hair greying results from activation of the sympathetic nerves that innervate the melanocyte stem-cell niche. Under conditions of stress, the activation of these sympathetic nerves leads to burst release of the neurotransmitter noradrenaline (also known as norepinephrine). This causes quiescent melanocyte stem cells to proliferate rapidly, and is followed by their differentiation, migration and permanent depletion from the niche. Transient suppression of the proliferation of melanocyte stem cells prevents stress-induced hair greying. Our study demonstrates that neuronal activity that is induced by acute stress can drive a rapid and permanent loss of somatic stem cells, and illustrates an example in which the maintenance of somatic stem cells is directly influenced by the overall physiological state of the organism.


Stress induces hair greying in mice through depletion of melanocyte stem cells, which is mediated by the activation of sympathetic nerves rather than through immune attack or adrenal stress hormones.


  
Improved protein structure prediction using potentials from deep learning 期刊论文
NATURE, 2020, 577 (7792) : 706-+
作者:  Ma, Runze;  Cao, Duanyun;  Zhu, Chongqin;  Tian, Ye;  Peng, Jinbo;  Guo, Jing;  Chen, Ji;  Li, Xin-Zheng;  Francisco, Joseph S.;  Zeng, Xiao Cheng;  Xu, Li-Mei;  Wang, En-Ge;  Jiang, Ying
收藏  |  浏览/下载:143/0  |  提交时间:2020/07/03

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence(1). This problem is of fundamental importance as the structure of a protein largely determines its function(2)  however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures(3). Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force(4) that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction(5) (CASP13)-a blind assessment of the state of the field-AlphaFold created high-accuracy structures (with template modelling (TM) scores(6) of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined(7).