Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (1): 25-33    DOI: 10.3785/j.issn.1008-9292.2019.02.05
    
Progress on structural biology of voltage-gated ion channels
SONG Fangjun1(),GUO Hongtao1,2()
Download: HTML( 23 )   PDF(1097KB)
Export: BibTeX | EndNote (RIS)      

Abstract  

Ion channels mediate ion transport across membranes, and play vital roles in processes of matter exchange, energy transfer and signal transduction in living organisms. Recently, structural studies of ion channels have greatly advanced our understanding of their ion selectivity and gating mechanisms. Structural studies of voltage-gated potassium channels elucidate the structural basis for potassium selectivity and voltage-gating mechanism; structural studies of voltage-gated sodium channels reveal their slow and fast inactivation mechanisms; and structural studies of transient receptor potential (TRP) channels provide complex and diverse structures of TRP channels, and their ligand gating mechanisms. In the article we summarize recent progress on ion channel structural biology, and outlook the prospect of ion channel structural biology in the future.

Key words： Ion channels      Protein structure      Ionselectivity      Voltage-gating      Ligand-gating      Review     
Received: 25 July 2018      Published: 10 May 2019
CLC:  Q615  
Corresponding Authors: GUO Hongtao     E-mail: fangjun_s@163.com;jiangtaoguo@zju.edu.cn
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
SONG Fangjun
GUO Hongtao
Cite this article:

SONG Fangjun,GUO Hongtao. Progress on structural biology of voltage-gated ion channels. J Zhejiang Univ (Med Sci), 2019, 48(1): 25-33.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.02.05     OR     http://www.zjujournals.com/med/Y2019/V48/I1/25


电压门控离子通道结构生物学研究进展

离子通道介导离子的跨膜运转，在生物体内的物质交换、能量传递和信号传导过程中发挥关键作用。近年来，离子通道结构生物学研究极大地推动了人们对离子通道的离子选择性和门控机制的认识。电压门控钾通道结构生物学研究阐明了钾离子选择性的结构基础和电压门控机制；电压门控钠通道结构生物学研究揭示了钠通道的慢失活和快失活机制；瞬时受体电位通道结构生物学研究提供了瞬时受体电位通道复杂多样的结构和配体门控机制。本文总结了近年来离子通道结构生物学的研究进展，并展望了未来离子通道结构生物学的发展。


关键词： 离子通道,  蛋白质结构,  离子选择性,  电压门控,  配体门控,  综述 
Figure 1 Overall architecture of ion channels
Figure 2 Structures of selectivity filters of KcsA, NavAb and TRPV6
Figure 3 Voltage gating mechanism of voltage-gated potassium channels
通道家族 通道名称 分辨率（nm） 状　态 结合配体或相互作用蛋白 参考文献

电压门控钾通道[border:border-top:solid;]

 KcsA 0.32 关闭态 Apo 1
KvAP 0.32 开放态 Apo 3
Kv1.2 0.29 开放态 氧化还原酶的β亚基 4-5
Kv1.2-2.1 0.24 开放态 嵌合体 6
Eag1 0.38 关闭态 钙调素 7
Slo1.1 0.35 开放态 Apo、钙离子 8-9
hERG1 0.38 开放态 Apo 10
KCNQ1 0.37 关闭态 钙调素 11

电压门控钠通道

 NavAb 0.27～0.32 预开放态、（慢）失活态 Apo，突变体 18, 20
NavRh 0.31 （慢）失活态 Apo 19
NavMs 0.25 开放态 Apo 21
Nav1.7 0.35 失活态 嵌合体，拮抗剂GX-936等 22
NavPaS 0.26～0.38 关闭态 Apo, 河豚毒素, 蛤蚌毒素, 蜘蛛毒素 23-24
EeNav1.4 0.40 开放态 β1亚基 25
Nav1.4 0.32 开放态 β1亚基 26
瞬时受体电位通道 TRPV1 0.38 关闭态、半开放态、开放态 Apo、辣椒素、双结毒素/树脂毒素 29-30
TRPA1 约0.40 关闭态 Apo、拮抗剂A-967079 32
TRPV2 0.31～0.50 关闭态、开放态 Apo、钙离子、树脂毒素 33-35
TRPV4 0.38 关闭态 Apo 36
TRPV5 0.48 关闭态 拮抗剂益康唑 37
TRPV6 0.33～0.40 关闭态、开放态 Apo，突变体 38-39
TRPP2 0.30～0.43 关闭态 Apo 40-42
TRPML1 0.35～0.37 关闭态、开放态 Apo、激动剂ML-SA1 43-44
TRPML3 0.29 关闭态 Apo 45
TRPM2 0.30～0.38 关闭态 钙离子，二磷酸腺苷核糖 46-47
TRPM4 0.29～0.38 关闭态 ATP、钙离子、十钒酸 48-51
TRPM8 0.41 未知 Apo 52
TRPC3 0.33～0.44 关闭态 Apo 53-54
TRPC4 0.33～0.36 关闭态 Apo 55-56
TRPC6 0.38 关闭态 抑制剂BTDM 53
NOMPC 0.36 关闭态 Apo 57
PKD2L1 0.34 开放态 Apo 58-59
Table 1 Statistics of Kv, Nav and TRP channel structures
Figure 4 Ligand gating mechanism of TRPML1
[1]   DOYLE D A , MORAIS C J , PFUETZNER R A , et al . The structure of the potassium channel: molecular basis of K+ conduction and selectivity[J]. Science,1998,280(5360):69-77.
[2]   YU F H , CATTERALL W A . The VGL-chanome: a protein superfamily specialized for electrical signaling and ionic homeostasis[J]. Sci STKE,2004,2004(253):re15.
[3]   JIANG Y , LEE A, CHEN J , et al . X-ray structure of a voltage-dependent K+ channel[J]. Nature,2003,423(6935):33-41.
[4]   LONG S B , CAMPBELL E B , MACKINNON R . Crystal structure of a mammalian voltage-dependent shaker family K+ channel[J]. Science,2005,309(5736):897-903.
[5]   LONG S B , CAMPBELL E B , MACKINNON R . Voltage sensor of Kv1.2: structural basis of electromechanical coupling[J]. Science,2005,309(5736):903-908.
[6]   LONG S B , TAO X , CAMPBELL E B , et al . Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment[J]. Nature,2007,450(7168):376-382.
[7]   WHICHER J R , MACKINNON R . Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism[J]. Science,2016,353(6300):664-669.
[8]   TAO X , HITE R K , MACKINNON R . Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel[J]. Nature,2017,541(7635):46-51.
[9]   HITE R K , TAO X , MACKINNON R . Structural basis for gating the high-conductance Ca2+-activated K+ channel[J]. Nature,2017,541(7635):52-57.
[10]   WANG W , MACKINNON R . Cryo-EM structure of the open human ether-à-go-go-related K+ channel hERG[J]. Cell,2017,169(3):422-430.e10.
[11]   SUN J , MACKINNON R . Cryo-EM structure of a KCNQ1/CaM complex reveals insights into congenital long QT syndrome[J]. Cell,2017,169(6):1042-1050.e9.
[12]   ZHOU Y , MORAIS-CABRAL J H , KAUFMAN A , et al . Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0?? resolution[J]. Nature,2001,414(6859):43-48.
[13]   YE S , LI Y , JIANG Y . Novel insights into K+ selectivity from high-resolution structures of an open K+ channel pore[J]. Nat Struct Mol Biol,2010,17(8):1019-1023.
[14]   SAUER D B , ZENG W , CANTY J , et al . Sodium and potassium competition in potassium-selective and non-selective channels[J]. Nat Commun,2013,4:2721.
[15]   TAO X , LEE A, LIMAPICHAT W , et al . A gating charge transfer center in voltage sensors[J]. Science,2010,328(5974):67-73.
[16]   TAKESHITA K , SAKATA S , YAMASHITA E , et al . X-ray crystal structure of voltage-gated proton channel[J]. Nat Struct Mol Biol,2014,21(4):352-357.
[17]   GUO J , ZENG W , CHEN Q , et al . Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana[J]. Nature,2016,531(7593):196-201.
[18]   PAYANDEH J , SCHEUER T , ZHENG N , et al . The crystal structure of a voltage-gated sodium channel[J]. Nature,2011,475(7356):353-358.
[19]   ZHANG X , REN W , DECAEN P , et al . Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel[J]. Nature,2012,486(7401):130-134.
[20]   PAYANDEH J , GAMAL E T M , SCHEUER T , et al . Crystal structure of a voltage-gated sodium channel in two potentially inactivated states[J]. Nature,2012,486(7401):135-139.
[21]   SULA A , BOOKER J , NG L C T, et al . The complete structure of an activated open sodium channel[J]. Nat Commun,2017,8:14205.
[22]   AHUJA S , MUKUND S , DENG L , et al . Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist[J]. Science,2015,350(6267):aac5464.
[23]   SHEN H , ZHOU Q , PAN X , et al . Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution[J]. Science,2017,355(6328):eaal4326.
[24]   SHEN H , LI Z , JIANG Y , et al . Structural basis for the modulation of voltage-gated sodium channels by animal toxins[J]. Science,2018,362(6412):eaau2596.
[25]   YAN Z , ZHOU Q , WANG L , et al . Structure of the Nav1.4-β1 complex from electric eel[J]. Cell,2017,170 (3):470-482.e11.
[26]   PAN X , LI Z , ZHOU Q , et al . Structure of the human voltage-gated sodium channel Nav1.4 in complex with β1[J]. Science,2018,362(6412):eaau2486.
[27]   NAYLOR C E , BAGNéRIS C , DECAEN P G , et al . Molecular basis of ion permeability in a voltage-gated sodium channel[J]. EMBO J,2016,35(8):820-830.
[28]   CLAPHAM D E , RUNNELS L W , STRüBING C . The TRP ion channel family[J]. Nat Rev Neurosci,2001,2(6):387-396.
[29]   CAO E , LIAO M , CHENG Y , et al . TRPV1 structures in distinct conformations reveal activation mechanisms[J]. Nature,2013,504(7478):113-118.
[30]   LIAO M , CAO E , JULIUS D , et al . Structure of the TRPV1 ion channel determined by electron cryo-microscopy[J]. Nature,2013,504(7478):107-112.
[31]   GAO Y , CAO E , JULIUS D , et al . TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action[J]. Nature,2016,534(7607):347-351.
[32]   PAULSEN C E , ARMACHE J P , GAO Y , et al . Structure of the TRPA1 ion channel suggests regulatory mechanisms[J]. Nature,2015,525(7570):552.
[33]   ZUBCEVIC L , HERZIK M A JR , CHUNG B C , et al . Cryo-electron microscopy structure of the TRPV2 ion channel[J]. Nat Struct Mol Biol,2016，23(2):180-186.
[34]   HUYNH K W , COHEN M R , JIANG J , et al . Structure of the full-length TRPV2 channel by cryo-EM[J]. Nat Commun,2016,7:11130.
[35]   ZUBCEVIC L , LE S , YANG H , et al . Conformational plasticity in the selectivity filter of the TRPV2 ion channel[J]. Nat Struct Mol Biol,2018，25(5):405-415.
[36]   DENG Z , PAKNEJAD N , MAKSAEV G , et al . Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms[J]. Nat Struct Mol Biol,2018,25(3):252-260.
[37]   TET H, LODOWSKI D T , HUYNH K W , et al . Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM[J]. Nat Struct Mol Biol,2018,25(1):53-60.
[38]   SAOTOME K , SINGH A K , YELSHANSKAYA M V , et al . Crystal structure of the epithelial calcium channel TRPV6[J]. Nature,2016,534(7608):506-511.
[39]   MCGOLDRICK L L , SINGH A K , SAOTOME K , et al . Opening of the human epithelial calcium channel TRPV6[J]. Nature,2018,553(7687):233-237.
[40]   SHEN P S , YANG X , DECAEN P G , et al . The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs[J]. Cell,2016,167(3):763-773.e11.
[41]   GRIEBEN M , PIKE A C W , SHINTRE C A , et al . Structure of the polycystic kidney disease TRP channel polycystin-2 (PC2)[J]. Nat Struct Mol Biol,2017,24(2):114-122.
[42]   WILKES M , MADEJ M G , KREUTER L , et al . Molecular insights into lipid-assisted Ca2+ regulation of the TRP channel polycystin-2[J]. Nat Struct Mol Biol,2017,24(2):123-130.
[43]   SCHMIEGE P , FINE M , BLOBEL G , et al . Human TRPML1 channel structures in open and closed conformations[J]. Nature,2017,550(7676):366-370.
[44]   CHEN Q , SHE J , ZENG W , et al . Structure of mammalian endolysosomal TRPML1 channel in nanodiscs[J]. Nature,2017,550(7676):415-418.
[45]   HIRSCHI M , HERZIK M A JR , WIE J, et al . Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3[J]. Nature,2017,550(7676):411-414.
[46]   ZHANG Z , TóTH B , SZOLLOSI A , et al . Structure of a TRPM2 channel in complex with Ca2 + explains unique gating regulation[J/OL]. Elife,2018,7:e36409.
[47]   HUANG Y , WINKLER P A , SUN W , et al . Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium[J]. Nature,2018,562(7725):145-149.
[48]   WINKLER P A , HUANG Y , SUN W , et al . Electron cryo-microscopy structure of a human TRPM4 channel[J]. Nature,2017,552(7684):200-204.
[49]   GUO J , SHE J , ZENG W , et al . Structures of the calcium-activated, non-selective cation channel TRPM4[J]. Nature,2017,552(7684):205-209.
[50]   AUTZEN H E , MYASNIKOV A G , CAMPBELL M G , et al . Structure of the human TRPM4 ion channel in a lipid nanodisc[J]. Science,2018,359(6372):228-232.
[51]   DUAN J , LI Z , LI J , et al . Structure of full-length human TRPM4[J]. Proc Natl Acad Sci U S A,2018,115(10):2377-2382.
[52]   YIN Y , WU M , ZUBCEVIC L , et al . Structure of the cold- and menthol-sensing ion channel TRPM8[J]. Science,2018,359(6372):237-241.
[53]   TANG Q , GUO W , ZHENG L , et al . Structure of the receptor-activated human TRPC6 and TRPC3 ion channels[J]. Cell Res,2018,28(7):746-755.
[54]   FAN C , CHOI W , SUN W , et al . Structure of the human lipid-gated cation channel TRPC3[ J/OL ]. Elife,2018,7:e36852.
[55]   VINAYAGAM D , MAGER T , APELBAUM A , et al . Electron cryo-microscopy structure of the canonical TRPC4 ion channel[J/OL]. Elife,2018,7:e36615.
[56]   DUAN J , LI J , ZENG B , et al . Structure of the mouse TRPC4 ion channel[J]. Nat Commun,2018,9(1):3102.
[57]   JIN P , BULKLEY D , GUO Y , et al . Electron cryo-microscopy structure of the mechanotransduction channel NOMPC[J]. Nature,2017,547(7661):118-122.
[58]   SU Q , HU F , LIU Y , et al . Cryo-EM structure of the polycystic kidney disease-like channel PKD2L1[J]. Nat Commun,2018,9(1):1192.
[1] Baboo Kalianee Devi, CHEN Zhengyun, ZHANG Xinmei. Progress on medical treatment in the management of adenomyosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 142-147.
[2] WU Binbin, YANG Yi. Biomarkers of cardiac surgery-associated acute kidney injury: a narrative review[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 224-229.
[3] YANG Kun, HU Xiaosheng. Research progress on miR-21 in heart diseases[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 214-218.
[4] XU Li, XU Ming, TONG Xiangmin. Effects of aerobic glycolysis on pathogenesis and drug resistance of non-Hodgkin lymphoma[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 219-223.
[5] ZHAO Shihao,ZHANG Xue,KE Yuehai. Progress on correlation between cell senescence and idiopathic pulmonary fibrosis[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 111-115.
[6] SHI Jing,FENG Jue. New inhibitors targeting bacterial RNA polymerase[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 44-49.
[7] SUN Boqiang,WANG Qiongyan,PAN Dongli. Mechanisms of herpes simplex virus latency and reactivation[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 89-101.
[8] SHEN Xiameng,LYU Weiguo. Research advances on the role of exosomes in chemotherapy resistance of ovarian cancer[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 116-120.
[9] XU Lizhen,YANG Fan. Structural modeling of selectivity filter in transient receptor pontential melastatin 8 ion channel[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 19-24.
[10] HONG Feifan,LI Yuezhou. Application of mechanosensitive channels in sonogenetics[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 34-38.
[11] XIAO Li,TONG Xiaoyong. Advances in molecular mechanism of vascular remodeling in pulmonary arterial hypertension[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 102-110.
[12] XIANG Yilang,WU Ziheng,ZHANG Hongkun. Progress on in situ fenestration during thoracic endovascular aortic repair[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 617-622.
[13] CAO Liqin,SHI Jimin. Graft failure in allogeneic hematopoietic stem cell trans-plantation[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 651-658.
[14] TANG Hexiao,BAI Yuquan,SHEN Wulin,ZHAO Jinping. Research progress on interleukin-6 in lung cancer[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 659-664.
[15] ZHAO Huihui,TANG Huifang. Research progress on composite animal models of inflammatory bowel disease based on gene knockout[J]. J Zhejiang Univ (Med Sci), 2018, 47(6): 665-670.