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DOI | 10.1126/science.aav0569 |
A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels | |
Schewe, Marcus1; Sun, Han2; Mert, Umit1; Mackenzie, Alexandra3,4,5; Pike, Ashley C. W.3; Schulz, Friederike1; Constantin, Cristina6,7; Vowinkel, Kirsty S.8; Conrad, Linus J.4,5; Kiper, Aytug K.8; Gonzalez, Wendy9,10; Musinszki, Marianne1; Tegtmeier, Marie1; Pryde, David C.11; Belabed, Hassane12; Nazare, Marc12; de Groot, Bert L.13; Decher, Niels8; Fakler, Bernd6,7; Carpenter, Elisabeth P.3,4; Tucker, Stephen J.4,5; Baukrowitz, Thomas1 | |
2019-02-22 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 363期号:6429页码:875-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Germany; England; Chile |
英文摘要 | Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+ channels gated at their selectivity filter (SF), including many two-pore domain K+ (K-2P) channels, voltage-gated hERG (human ether-a-go-go-related gene) channels and calcium (Ca2+)-activated big-conductance potassium (BK)-type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+ occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+ channel activators and highlight a filter gating machinery that is conserved across different families of K+ channels with implications for rational drug design. |
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:000459387100045 |
WOS关键词 | MOLECULAR-DYNAMICS SIMULATIONS ; PARTICLE MESH EWALD ; POTASSIUM CHANNELS ; CONSTANT-PRESSURE ; STRUCTURAL BASIS ; HIGH-THROUGHPUT ; BK CHANNELS ; HERG ; CONDUCTANCE ; K-2P |
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/200815 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Christian Albrechts Univ Kiel, Inst Physiol, D-24118 Kiel, Germany; 2.Leibniz Forschungsinst Mol Pharmakol FMP, Dept Biol Struct, D-13125 Berlin, Germany; 3.Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ, England; 4.Univ Oxford, OXION Initiat Ion Channels & Dis, Oxford OX1 3PN, England; 5.Univ Oxford, Dept Phys, Clarendon Lab, Oxford OX1 3PU, England; 6.Albert Ludwigs Univ Freiburg, Inst Physiol 2, D-79104 Freiburg, Germany; 7.Ctr Biol Signaling Studies CIBSS & BIOSS, D-79104 Freiburg, Germany; 8.Philipps Univ Marburg, Inst Physiol & Pathophysiol, Vegetat Physiol, D-35037 Marburg, Germany; 9.Univ Talca, Ctr Bioinformat & Simulac Mol, Talca 3465548, Chile; 10.Univ Talca, Millennium Nucleus Ion Channels Associated Dis Mi, Talca 3465548, Chile; 11.Pfizer Worldwide Med Chem, Neurosci & Pain Res Unit, Portway Bldg,Granta Pk, Great Abington CB21 6GS, Cambs, England; 12.Leibniz Forschungsinst Mol Pharmakol FMP, Dept Med Chem, D-13125 Berlin, Germany; 13.Max Planck Inst Biophys Chem, Computat Biomol Dynam Grp, D-37077 Gottingen, Germany |
推荐引用方式 GB/T 7714 | Schewe, Marcus,Sun, Han,Mert, Umit,et al. A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels[J]. SCIENCE,2019,363(6429):875-+. |
APA | Schewe, Marcus.,Sun, Han.,Mert, Umit.,Mackenzie, Alexandra.,Pike, Ashley C. W..,...&Baukrowitz, Thomas.(2019).A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels.SCIENCE,363(6429),875-+. |
MLA | Schewe, Marcus,et al."A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels".SCIENCE 363.6429(2019):875-+. |
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