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| Open AccessDirect observation of the conformational states of PIEZO1
The plasma membrane can expand the blades of the PIEZO1 ion channel, impacting channel activation.
- Eric M. Mulhall
- , Anant Gharpure
- & Ardem Patapoutian
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Article
| Open AccessCFTR function, pathology and pharmacology at single-molecule resolution
A structure–function analysis of cystic fibrosis transmembrane conductance regulator shows its two nucleotide-binding domains dimerize before channel opening, and reveals a mechanism through which conformational changes in the channel regulate chloride conductance.
- Jesper Levring
- , Daniel S. Terry
- & Jue Chen
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Article |
Bestrophin-2 and glutamine synthetase form a complex for glutamate release
Electrophysiological, structural and biochemical studies on the bestrophin-2 anion channel reveal asymmetric permeability to glutamate and show that it forms a cooperative machinery in complex with glutamine synthetase for glutamate release.
- Aaron P. Owji
- , Kuai Yu
- & Tingting Yang
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Article |
cAMP binding to closed pacemaker ion channels is non-cooperative
Direct monitoring of individual cAMP molecules binding to HCN ion channels reveals the binding dynamics underlying the distinct physiological responses of ion channel isoforms.
- David S. White
- , Sandipan Chowdhury
- & Baron Chanda
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Article |
Structures and pH-sensing mechanism of the proton-activated chloride channel
Cryo-electron microscopy structures of the human proton-activated chloride channel (PAC) shed light on its pH-dependent gating mechanism and anion selectivity.
- Zheng Ruan
- , James Osei-Owusu
- & Wei Lü
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Structures of human pannexin 1 reveal ion pathways and mechanism of gating
Cryo-electron microscopy structures of the ATP-permeable channel pannexin 1 reveal a gating mechanism involving multiple distinct ion-conducting pathways.
- Zheng Ruan
- , Ian J. Orozco
- & Wei Lü
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Article |
Electromechanical coupling in the hyperpolarization-activated K+ channel KAT1
The cryo-electron microscopy structure of the hyperpolarization-activated K+ channel KAT1 points to a direct-coupling mechanism between S4 movement and the reorientation of the C-linker.
- Michael David Clark
- , Gustavo F. Contreras
- & Eduardo Perozo
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Article |
Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex
Cryo-electron microscopy reveals the structures of the mitochondrial calcium uniporter holocomplex in low- and high-calcium conditions, showing the gating mechanism that underlies uniporter activation in response to intracellular calcium signals.
- Minrui Fan
- , Jinru Zhang
- & Liang Feng
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Article |
The structures and gating mechanism of human calcium homeostasis modulator 2
Cryo-electron microscopy structures of the active and inhibited human CALHM2 channel suggest a two-stage gating mechanism in which the S1 helix adjusts the pore size, which is then fine-tuned by the N-terminal helix.
- Wooyoung Choi
- , Nicolina Clemente
- & Wei Lü
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Article |
Identification of an ATP-sensitive potassium channel in mitochondria
The pore-forming and ATP-binding subunits of a mitochondrial protein complex that mediates ATP-dependent potassium currents are identified and characterized, revealing the role of this channel in mitochondrial physiology and pathologies.
- Angela Paggio
- , Vanessa Checchetto
- & Diego De Stefani
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Article |
GABAA receptor signalling mechanisms revealed by structural pharmacology
Cryo-electron microscopy structures are reported in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA, and the benzodiazepines alprazolam and diazepam.
- Simonas Masiulis
- , Rooma Desai
- & A. Radu Aricescu
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Letter |
Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer
A high-resolution cryo-electron microscopy structure is reported for the full-length human α1β3γ2L GABAA receptor, functionally reconstituted in lipid nanodiscs.
- Duncan Laverty
- , Rooma Desai
- & A. Radu Aricescu
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Article |
Structure of native lens connexin 46/50 intercellular channels by cryo-EM
Cryo-electron microscopy structures of connexin channels composed of connexin 46 and connexin 50 in an open-state reveal features that govern permselectivity and the location of mutated residues linked to herediatry cataracts.
- Janette B. Myers
- , Bassam G. Haddad
- & Steve L. Reichow
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Letter |
Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor
Cryo-electron microscopy structures of the serotonin-bound 5-HT3A serotonin receptor show the receptor populating two distinct states, characterized by twisting in the extracellular and transmembrane domains relative to the apo state, which creates pathways for ion permeation.
- Sandip Basak
- , Yvonne Gicheru
- & Sudha Chakrapani
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Letter |
Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium
Structures of the transient receptor potential melastatin 2 channel in the apo resting (closed) state and in the ADP-ribose/Ca2+-bound active (open) state are determined by cryo-electron microscopy.
- Yihe Huang
- , Paige A. Winkler
- & Juan Du
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Article |
X-ray and cryo-EM structures of the mitochondrial calcium uniporter
X-ray and cryo-electron microscopy structures of fungal mitochondrial calcium uniporter proteins reveal a tetrameric architecture and shed light on the function of the channel.
- Chao Fan
- , Minrui Fan
- & Liang Feng
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Article |
Structure of a human synaptic GABAA receptor
The cryo-electron microscopy structure of the type A GABA receptor bound to GABA and the benzodiazepine site antagonist flumazenil reveals structural mechanisms that underlie intersubunit interactions and ligand selectivity of the receptor.
- Shaotong Zhu
- , Colleen M. Noviello
- & Ryan E. Hibbs
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Article |
Structure of a volume-regulated anion channel of the LRRC8 family
The structure of a homomeric channel of subunit A of leucine-rich repeat-containing protein 8 (LRRC8) determined by cryo-electron microscopy and X-ray crystallography reveals the basis for anion selectivity.
- Dawid Deneka
- , Marta Sawicka
- & Raimund Dutzler
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Article |
Structure of the mechanically activated ion channel Piezo1
The cryo-electron microscopy structure of full-length mouse Piezo1 reveals six Piezo repeats, and 26 transmembrane helices per protomer, and shows that a kinked helical beam and anchor domain link the Piezo repeats to the pore and control gating allosterically.
- Kei Saotome
- , Swetha E. Murthy
- & Andrew B. Ward
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Letter |
Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM
Cryo-electron microscopy mapping of the calcium-activated chloride channel TMEM16A combined with functional experiments reveals that calcium ions interact directly with the pore to activate the channel.
- Cristina Paulino
- , Valeria Kalienkova
- & Raimund Dutzler
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Article |
Electron cryo-microscopy structure of a human TRPM4 channel
The structure of the Ca2+-activated, non-selective ion channel TRPM4 bound to the agonist Ca2+ and a modulator decavanadate, solved using electron cryo-microscopy.
- Paige A. Winkler
- , Yihe Huang
- & Wei Lü
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Letter |
Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3
A cryo-electron microscopy structure shows that the mucolipin domain of the lysosomal calcium channel TRPML3 binds phosphatidylinositol-3,5-bisphosphate and gates the channel.
- Marscha Hirschi
- , Mark A. Herzik Jr
- & Seok-Yong Lee
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Letter |
K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site
Crystal structures of an activated two-pore potassium channel reveal a cryptic binding pocket that binds small-molecule activators that restrict the mobility of the selectivity filter and surrounding structure, stabilizing an active ‘leak-mode’ conformation.
- Marco Lolicato
- , Cristina Arrigoni
- & Daniel L. Minor Jr
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Letter |
Electron cryo-microscopy structure of the mechanotransduction channel NOMPC
Single-particle electron cryo-microscopy analysis of the mechanotransduction channel NOMPC reveals that it contains a bundle of four helical spring-shaped ankyrin repeat domains that undergo motion, potentially allowing mechanical movement of the cytoskeleton to be coupled to the opening of the channel.
- Peng Jin
- , David Bulkley
- & Yifan Cheng
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Letter |
Crystal structure of the potassium-importing KdpFABC membrane complex
The crystal structure of the bacterial potassium import complex KdpFABC shows how ATP hydrolysis is coupled to potassium transport to maintain cellular homeostasis under low potassium conditions.
- Ching-Shin Huang
- , Bjørn Panyella Pedersen
- & David L. Stokes
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Letter |
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Conditional deletion of the mitochondrial Na+/Ca2+ exchanger NCLX in adult mouse hearts causes sudden death due to mitochondrial calcium overload, whereas its overexpression limits cell death elicited by ischaemia reperfusion injury and heart failure.
- Timothy S. Luongo
- , Jonathan P. Lambert
- & John W. Elrod
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Article |
Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel
Two complementary studies present the full-length high-resolution structure of a Slo1 channel in the presence or absence of Ca2+ ions, in which an unconventional allosteric voltage-sensing mechanism regulates the Ca2+ sensor in addition to the voltage sensor’s direct action on the pore.
- Xiao Tao
- , Richard K. Hite
- & Roderick MacKinnon
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Article |
Structural basis for gating the high-conductance Ca2+-activated K+ channel
Two complementary studies present the full-length high-resolution structure of a Slo1 channel in the presence or absence of Ca2+ ions, in which an unconventional allosteric voltage-sensing mechanism regulates the Ca2+ sensor in addition to the voltage sensor’s direct action on the pore.
- Richard K. Hite
- , Xiao Tao
- & Roderick MacKinnon
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Letter |
X-ray structure of the human α4β2 nicotinic receptor
Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission; here, the first X-ray crystal structure of a nicotinic receptor is reported, revealing how nicotine stabilizes the receptor in a non-conducting, desensitized conformation.
- Claudio L. Morales-Perez
- , Colleen M. Noviello
- & Ryan E. Hibbs
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Article |
Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution
The cryo-electron microscopy structure of the rabbit voltage-gated calcium channel Cav1.1 complex at a nominal resolution of 3.6 ångströms.
- Jianping Wu
- , Zhen Yan
- & Nieng Yan
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Letter |
Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs
Calcium channel blockers are widely used to treat cardiovascular diseases; new structural studies uncover how two different types of calcium-channel blockers bind to the channel; the drugs bind in different locations, revealing different mechanisms of drug action.
- Lin Tang
- , Tamer M. Gamal El-Din
- & William A. Catterall
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Letter |
Architecture of fully occupied GluA2 AMPA receptor–TARP complex elucidated by cryo-EM
The cryo-electron microscopy structure of the homomeric GluA2 AMPA receptor in the presence of TARP γ2 subunits is reported, which reveals that TARPs are arranged around the ion channel domain and underneath the ligand-binding domains, poised to modulate receptor activity.
- Yan Zhao
- , Shanshuang Chen
- & Eric Gouaux
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Article |
Crystal structure of the epithelial calcium channel TRPV6
The X-ray crystal structure of rat transient receptor potential channel TRPV6 at 3.25 Å resolution is reported, providing new insights into its assembly and calcium-selective permeation.
- Kei Saotome
- , Appu K. Singh
- & Alexander I. Sobolevsky
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Article |
Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain
Two spider toxins are shown to target the Nav1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling.
- Jeremiah D. Osteen
- , Volker Herzig
- & David Julius
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Article |
TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action
Cryo-electron microscopy has undergone a resolution revolution—here, this method has been combined with lipid nanodisc technology to solve structures of TRPV1, the receptor for capsaicin, in a membrane bilayer, revealing mechanisms of lipid and ligand regulation.
- Yuan Gao
- , Erhu Cao
- & Yifan Cheng
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Letter |
Architecture of the mitochondrial calcium uniporter
The structure of the core region of the mitochondrial calcium uniporter (MCU) is determined by NMR and electron microscopy, revealing that MCU is a homo-pentamer with a specific transmembrane helix forming a hydrophilic pore across the membrane, and representing one of the largest membrane protein structures characterized by NMR spectroscopy.
- Kirill Oxenoid
- , Ying Dong
- & James J. Chou
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Letter |
Daily magnesium fluxes regulate cellular timekeeping and energy balance
Circadian rhythms in the intracellular concentration of magnesium ions act as a cell-autonomous timekeeping component to determine key clock properties and tune cellular metabolism both in a human cell line and in a unicellular alga.
- Kevin A. Feeney
- , Louise L. Hansen
- & Gerben van Ooijen
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Letter |
Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana
The X-ray crystal structure of a two-pore channel from Arabidopsis thaliana is reported, revealing the mechanisms of ion permeation, inhibition channel activation, and location of regulatory sites and voltage-sensing domains.
- Alexander F. Kintzer
- & Robert M. Stroud
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Article |
Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana
The X-ray crystal structure of a two-pore channel from Arabidopsis thaliana reveals the structure and the mechanism of voltage gating of this class of ubiquitous cation-selective ion channels.
- Jiangtao Guo
- , Weizhong Zeng
- & Youxing Jiang
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Article |
Gating machinery of InsP3R channels revealed by electron cryomicroscopy
This study has determined the electron cryomicroscopy structure of the mammalian type 1 InsP3 receptor in a ligand-free state at 4.7 Å resolution; although the central Ca2+-conduction pathway is similar to other ion channels, the unique architecture of the C-terminal domains of the tetrameric channel suggests that a distinctive allosteric mechanism underlies the activation of InsP3 gating.
- Guizhen Fan
- , Matthew L. Baker
- & Irina I. Serysheva
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Article |
Cryo-electron microscopy structure of the Slo2.2 Na+-activated K+ channel
The structure of the full-length Slo2.2 Na+-activated K+ channel is determined by cryo-electron microscopy, revealing features that explain the high conductance and gating mechanism of the Slo K+ channel family.
- Richard K. Hite
- , Peng Yuan
- & Roderick MacKinnon
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Letter |
Crystal structure of human glycine receptor-α3 bound to antagonist strychnine
The X-ray crystal structure of the human glycine receptor in the presence of strychnine, an antagonist, reveals how antagonist binding leads to closure of the channel pore.
- Xin Huang
- , Hao Chen
- & Paul L. Shaffer
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Article |
Architecture of the mammalian mechanosensitive Piezo1 channel
Piezo1, a mechanosensitive cation channel, senses shear stress of blood flow for proper blood vessel development, regulates red blood cell function and controls cell migration and differentiation; here a trimeric architecture of this novel class of ion channel is reported, suggesting that Piezo1 may use its peripheral propeller-like ‘blades’ as force sensors to gate the central ion-conducting pore.
- Jingpeng Ge
- , Wanqiu Li
- & Maojun Yang
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Article |
Glycine receptor mechanism elucidated by electron cryo-microscopy
A high-resolution electron cryo-microscopy structure of the zebrafish α1 glycine receptor bound to agonists or antagonists reveals the conformational changes that take place when the channel transitions from closed to open state.
- Juan Du
- , Wei Lü
- & Eric Gouaux
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Letter |
Crystal structures of a double-barrelled fluoride ion channel
Microorganisms can export toxic fluoride ions through highly selective channels of the Fluc family; here, the crystal structures of two bacterial Fluc homologues are presented, revealing that selectivity for small F− ions may arise from the proteins’ narrow pores and unusual anion coordination.
- Randy B. Stockbridge
- , Ludmila Kolmakova-Partensky
- & Simon Newstead
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Article |
Structure of the TRPA1 ion channel suggests regulatory mechanisms
The high-resolution electron cryo-microscopy structure of the full-length human TRPA1 ion channel is presented; the structure reveals a unique ankyrin repeat domain arrangement, a tetrameric coiled-coil in the centre of the channel that acts as a binding site for inositol hexakisphosphate, an outer poor domain with two pore helices, and a new drug binding site, findings that collectively provide mechanistic insight into TRPA1 regulation.
- Candice E. Paulsen
- , Jean-Paul Armache
- & David Julius
-
Article |
Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution
Using electron cryomicroscopy, the structure of the closed-state rabbit ryanodine receptor RyR1 in complex with its modulator FKBP12 is solved at 3.8 Å; in addition to determining structural details of the ion-conducting channel domain, three previously uncharacterized domains help to reveal a molecular scaffold that allows long-range allosteric regulation of channel activities.
- Zhen Yan
- , Xiao-chen Bai
- & Nieng Yan
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Letter |
Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel
X-ray structures of the human TRAAK mechanosensitive potassium channel reveal how build-up of tension in the lipid membrane can convert the channel from a non-conducting wedge shape associated with an inserted lipid acyl chain that blocks the pore to an expanded cross-sectional shape that prevents lipid entry and thus permits ion conduction.
- Stephen G. Brohawn
- , Ernest B. Campbell
- & Roderick MacKinnon
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Article |
Structure of a mammalian ryanodine receptor
Using electron cryomicroscopy, the closed-state structure of rabbit RyR1 is determined at 4.8 Å resolution; analysis confirms that the RyR1 architecture consists of a six-transmembrane ion channel with a cytosolic α-solenoid scaffold, and suggests a mechanism for Ca2+-induced channel opening.
- Ran Zalk
- , Oliver B. Clarke
- & Andrew R. Marks