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| Open AccessNative American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.
- Rían W. Manville
- , J. Alfredo Freites
- & Geoffrey W. Abbott
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Article
| Open AccessStructural mapping of Nav1.7 antagonists
Voltage-gated sodium (Nav) channels are targeted by various clinically applied and investigational drugs. Here cryo-EM structures of Nav1.7 bound to 7 compounds with diverse chemical skeletons reveal the structural basis of action of these drugs and provide a 3D structural map for drug binding sites on Nav channels.
- Qiurong Wu
- , Jian Huang
- & Nieng Yan
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Article
| Open AccessStructural interplay of anesthetics and paralytics on muscle nicotinic receptors
Here the authors use a structural approach to reveal how neuromuscular blockers and a general anesthetic antagonize the muscle-type nicotinic receptor through competitive and allosteric mechanisms.
- Umang Goswami
- , Md Mahfuzur Rahman
- & Ryan E. Hibbs
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Article
| Open AccessAnt venoms contain vertebrate-selective pain-causing sodium channel toxins
Stings of certain ant species can cause intense, long-lasting nociception. Here, authors show that the major contributors of these symptoms are vertebrate-selective defensive venom peptides which modulate the activity of voltage-gated sodium channels.
- Samuel D. Robinson
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessMolecular mechanism of hyperactivation conferred by a truncation of TRPA1
A drastic TRPA1 mutant was identified in patients with CRAMPT syndrome, but it has not been functionally characterized. Here, the authors find this mutant confers gain-of-function by co-assembling with wild type protein to form hyperactive channels.
- Avnika Bali
- , Samantha P. Schaefer
- & Candice E. Paulsen
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Article
| Open AccessVesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry
In glutamatergic neurons, synaptic vesicles contain glutamate, but not aspartate. Here, the authors show that vesicular glutamate transporters are H+/anion exchangers that attain high selectivity for glutamate via variable transport coupling.
- Bettina Kolen
- , Bart Borghans
- & Christoph Fahlke
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Article
| Open AccessTwo single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1
TRPV1 is a noxious heat sensor. Here, authors showed that tailed amphibians express TRPV1 with a reduced heat-activation threshold by substitution of two amino acids in the N-terminal region to contribute to cool-habitat selection.
- Shogo Hori
- , Michihiro Tateyama
- & Osamu Saitoh
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Article
| Open AccessStructural mechanisms of TRPM7 activation and inhibition
Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists.
- Kirill D. Nadezhdin
- , Leonor Correia
- & Alexander I. Sobolevsky
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Article
| Open AccessMolecular architecture of the Gαi-bound TRPC5 ion channel
Ion channels could be directly regulated by the alpha subunit of heterotrimeric G-proteins. Here, authors present the cryo-EM structure of an ion channel-Gα complex, TRPC5-Gαi3, and present functional insights into their direct interaction.
- Jongdae Won
- , Jinsung Kim
- & Hyung Ho Lee
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Article
| Open AccessPain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
Voltage-gated sodium channels function as multiprotein signaling complexes. Here, authors show that the dispanin TMEM233 is essential for activity of stinging nettle toxins and that co-expression of TMEM233 modulates the gating properties of NaV1.7.
- Sina Jami
- , Jennifer R. Deuis
- & Irina Vetter
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Article
| Open AccessHuman TRPV1 structure and inhibition by the analgesic SB-366791
Small molecules targeting transient receptor potential (TRP) channels might be used to control pain. Here, Neuberger et al. report cryo-EM structures of human TRPV1 in the absence of added ligands or in the presence of the TRPV1-specific antagonist SB-366791, providing insights for the design of new promising analgesics.
- Arthur Neuberger
- , Mai Oda
- & Alexander I. Sobolevsky
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Article
| Open AccessDerepression may masquerade as activation in ligand-gated ion channels
Ligand-gated ion channels are activated/opened by agonists. Tessier et al. show that agonists can inhibit the inhibition of intrinsic basal activity, and thus that activation may instead be the manifestation of a derepression mechanism.
- Christian J. G. Tessier
- , Johnathon R. Emlaw
- & Corrie J. B. daCosta
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Article
| Open AccessStructural and functional analysis of human pannexin 2 channel
The PANX2 channel is involved in skin homeostasis and neuronal development, but the molecular basis of channel function remains largely unknown. Here, the authors provide detailed analysis of the structure, function, and pharmacology of human PANX2.
- Zhihui He
- , Yonghui Zhao
- & Peng Yuan
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Article
| Open AccessModulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics
AMPA receptors associated with TARP subunits enable the development of selective AMPA receptor drugs. Here, the authors provide cryo-EM structures of receptors bound to three TARP-γ8 selective drugs, and reveal bifunctionality of one ligand.
- Danyang Zhang
- , Remigijus Lape
- & Ingo H. Greger
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Article
| Open AccessTwo gates mediate NMDA receptor activity and are under subunit-specific regulation
NMDA receptors are glutamate-gated ion channels that regulate fast signaling in the brain. Here, the authors show that the opening and closing patterns of the channel derive from the action of two gates that are regulated by distinct subunits.
- Johansen B. Amin
- , Miaomiao He
- & Lonnie P. Wollmuth
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Article
| Open AccessMechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel
Human Eag2 is a voltage-gated potassium channel with unique delayed rectifying gating kinetics. Here, authors show how voltage opens the channel and illuminate a mechanism of delayed rectifier gating.
- Mingfeng Zhang
- , Yuanyue Shan
- & Duanqing Pei
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Article
| Open AccessConformational transitions and allosteric modulation in a heteromeric glycine receptor
Glycine receptors (GlyR) are a critical postsynaptic component of spinal neurons. Here, the auhtors present cryo-EM structures of a heteromeric GlyR in the presence of an antagonist, agonist and agonist with a positive allosteric modulator.
- Eric Gibbs
- , Emily Klemm
- & Sudha Chakrapani
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Article
| Open AccessPhotocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1
The Ca2+ ion channel Orai1 is crucial in immune cells. Here, the authors applied genetic code expansion to transfer light-sensitivity to the Orai1 channel and achieved precise control over its function.
- Lena Maltan
- , Sarah Weiß
- & Isabella Derler
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Article
| Open AccessOptical control of PIEZO1 channels
PIEZO proteins are large, mechanically-activated trimeric ion channels. Here the authors report a light-gated mouse PIEZO1 channel, mOP1, whereby an azobenzene-based photoswitch covalently localised at the extracellular apex of a transmembrane helix, rapidly triggers channel gating on light irradiation.
- Francisco Andrés Peralta
- , Mélaine Balcon
- & Thomas Grutter
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Article
| Open AccessA photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals
Research on pain often relies on animals, and there is always a need for more precise and more ethical tools. Here, authors present a light-activatable molecule that induces pain in freely moving animal models in a reversible, non-invasive, and spatiotemporally defined way.
- Arnaud Landra-Willm
- , Ameya Karapurkar
- & Guillaume Sandoz
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Article
| Open AccessNoncanonical electromechanical coupling paths in cardiac hERG potassium channel
Potassium channels allow vital organ such as brain, heart, and muscles to function. Here, authors reveal the existence of a noncanonical kinematic chain of residues involving the S4/S1 and S1/S5 subunit interfaces that controls the gating of the hERG cardiac channel.
- Carlos A. Z. Bassetto Jr
- , Flavio Costa
- & Alberto Giacomello
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Article
| Open AccessMembrane phospholipids control gating of the mechanosensitive potassium leak channel TREK1
Tandem pore (K2P) potassium channels set the cellular resting membrane potential in tissues throughout the body. Here, authors show how the composition of phospholipid within the bilayer may directly alter gating in this family of ion channels.
- Philipp A. M. Schmidpeter
- , John T. Petroff II
- & Paul M. Riegelhaupt
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Article
| Open AccessA bivalent remipede toxin promotes calcium release via ryanodine receptor activation
Insect toxins with tandem repeats of neurotoxin domains have been found with enhanced receptor avidity. Here, the authors describe a bivalent toxin from remipede venom that targets ryanodine receptors, a rare target for animal venoms.
- Michael J. Maxwell
- , Chris Thekkedam
- & Mehdi Mobli
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Article
| Open AccessStructure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin
NaV1.6 channel plays a critical role in neuronal excitability. Here, authors present human NaV1.6 structures in apo and 4,9-anhydro-tetrodotoxin bound forms, which reveal molecular mechanisms of NaV1.6 Na+ conductance and inhibition by the blocker.
- Yue Li
- , Tian Yuan
- & Daohua Jiang
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Article
| Open AccessConformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM
Gap junction intercellular channels (GJIChs) facilitate direct communication between adjacent cells. Here, authors provide high-resolution information on dynamic structural changes in Cx43 GJICh that are necessary to understand the gating mechanism.
- Hyuk-Joon Lee
- , Hyung Jin Cha
- & Jae-Sung Woo
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Article
| Open AccessIllumination of a progressive allosteric mechanism mediating the glycine receptor activation
Glycine receptors are channel receptors mediating signal transduction between neurons that transit between resting and open states upon neurotransmitter binding. Here, the authors illuminate a progressive transition of opening by combining voltage-clamp fluorometry and molecular dynamics.
- Sophie Shi
- , Solène N. Lefebvre
- & Pierre-Jean Corringer
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Article
| Open AccessMolecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3
The CaV2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human CaV2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.
- Yiwei Gao
- , Shuai Xu
- & Yan Zhao
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Article
| Open AccessA gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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Article
| Open AccessConformational plasticity of NaK2K and TREK2 potassium channel selectivity filters
The potassium channel selectivity filter is responsible for conduction and selectivity of K + over other cations. Here, the authors use a combination of single molecule FRET, non-canonical fluorescent amino acid incorporation, and single channel patch-clamp electrophysiology, to establish the generality of K + -induced SF conformational stability across the K + channel superfamily.
- Marcos Matamoros
- , Xue Wen Ng
- & Colin G. Nichols
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Article
| Open AccessStructure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
TRPV1 as a drug target suffers from side effects of hypothermia. Here, authors engineer a peptide, sRhTx, as a positive allosteric modulator of TRPV1 channel. It potentiates the activity of TRPV1 to reversibly ablate pain-sensing nerve terminals for long-lasting analgesia without changing mice body temperature.
- Heng Zhang
- , Jia-Jia Lin
- & Fan Yang
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Article
| Open AccessVertebrate OTOP1 is also an alkali-activated channel
pH sensation is critical for survival of vertebrates. Here, authors found six vertebrate OTOP1 channels that were highly conserved and directly activated by extracellular alkali. Key mutations of OTOP1 reduced alkali affinity without affecting acid activation.
- Lifeng Tian
- , Hao Zhang
- & Ren Lai
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| Open AccessRegulating voltage-gated ion channels with nanobodies
In this work, Morgenstern and colleagues describe an approach involving functionalized nanobodies which decrease the activity of voltage-gated Ca2+ channels associated with β1 subunits and promote their removal from the surface membrane of neurons and muscle.
- Declan Manning
- & L. Fernando Santana
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Article
| Open AccessSelective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody
Auxiliary subunit molecular diversity is an unexploited target for developing ion channel inhibitors. Here, the authors develop a general approach to inhibit ion channels based on the resident auxiliary subunit isoform to elucidate unique functions of distinct ion channel macromolecular complexes.
- Travis J. Morgenstern
- , Neha Nirwan
- & Henry M. Colecraft
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Article
| Open AccessBackbone amides are determinants of Cl− selectivity in CLC ion channels
CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl− specificity within this family of ion channels.
- Lilia Leisle
- , Kin Lam
- & Alessio Accardi
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Article
| Open AccessCannabinoid non-cannabidiol site modulation of TRPV2 structure and function
TRPV2 is activated by temperature and cannabinoids. Here, the authors have used cryo-EM and electrophysiology to identify a cannabinoid binding site distinct from that of cannabidiol as a possible drug target for treatment of inflammation and immune-mediated diseases.
- Liying Zhang
- , Charlotte Simonsen
- & Peter M. Zygmunt
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Article
| Open AccessMembrane curvature governs the distribution of Piezo1 in live cells
This study demonstrates that the curvature of the cell membrane directly regulates the spatial distribution of Piezo1, a widely expressed mechanosensitive ion channel. Piezo1 may flatten upon activation and can mechanically inhibit membrane dynamics
- Shilong Yang
- , Xinwen Miao
- & Zheng Shi
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Article
| Open AccessStructures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments
Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.
- Xia Yao
- , Yan Wang
- & Nieng Yan
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Article
| Open AccessOpen-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation
Pentameric ligand-gated ion channels are modulated by anionic phospholipids. Here, by capturing an open-channel conformation of ELIC, the authors demonstrate the structural details of channel activation and a leaflet-specific mechanism for modulation by phosphatidylglycerol.
- John T. Petroff II
- , Noah M. Dietzen
- & Wayland W. L. Cheng
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Article
| Open AccessConformational motions and ligand-binding underlying gating and regulation in IP3R channel
Here authors report cryo-EM structures of IP3R1 which provide atomic details of IP3, Ca2+ and ATP binding. Molecular motions of key domains and sidechains were found to regulate ligand binding and gating, which are validated by functional assays.
- Guizhen Fan
- , Mariah R. Baker
- & Irina I. Serysheva
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Article
| Open AccessGating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel
Visualizing conformational changes during ion channel gating is crucial to understand their regulation. Here, Gao et al. capture multiple gating intermediates in a CNG channel as well as subtle, lateral voltage sensor movements necessary for channel opening.
- Xiaolong Gao
- , Philipp A. M. Schmidpeter
- & Crina M. Nimigean
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Article
| Open AccessCapture at the ER-mitochondrial contacts licenses IP3 receptors to stimulate local Ca2+ transfer and oxidative metabolism
The formation and dissolution of ER-Mitochondria contacts is unclear. Here, authors show that the IP3 receptor traffics in and out of the contacts and, when trapped, improves calcium signaling to stimulate energy metabolism.
- Máté Katona
- , Ádám Bartók
- & György Hajnóczky
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Article
| Open AccessAn allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
Ca2+ activated BK channels are important for neural and muscle function. Here authors use a compound, BC5, to show that the interface between the cytosolic and voltage sensing domains is a major allosteric pathway for Ca2+ binding to open the channel.
- Guohui Zhang
- , Xianjin Xu
- & Jianmin Cui
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Article
| Open AccessStructural basis for the activation of the lipid scramblase TMEM16F
TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.
- Melanie Arndt
- , Carolina Alvadia
- & Raimund Dutzler
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Article
| Open AccessGi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
Gi/o protein-coupled receptors (Gi/o-GPCRs) limit β-cell insulin secretion by decreasing Ca2+ entry; however, the underlying mechanism has not been identified. Here, the authors show that Gi/o-GPCRs hyperpolarize mouse and human β-cell membrane potential by activating Na+/K+ATPases.
- Matthew T. Dickerson
- , Prasanna K. Dadi
- & David A. Jacobson
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Article
| Open AccessThe human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain
The authors report how the cold and heat sensing properties of the pain receptor TRPA1 are separately modulated by the C-terminal intracellular domain, and in concert with either the S1–S4 or the S5–S6 transmembrane domain.
- Lavanya Moparthi
- , Viktor Sinica
- & Peter M. Zygmunt
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Article
| Open AccessStructural basis for the activity regulation of a potassium channel AKT1 from Arabidopsis
Arabidopsis thaliana potassium channel AKT1 is responsible for primary K + uptake from soil, which is functionally activated through phosphorylation and negatively regulated by an α-subunit AtKC1. Here, the authors report the structures of AKT1 at different states, revealing a 2- fold to 4-fold symmetry switch at cytoplasmic domain associated with AKT1 activity regulation.
- Yaming Lu
- , Miao Yu
- & Guanghui Yang
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Article
| Open AccessStructural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs
Glycine receptors (GlyRs) mediate motor control and pain perception. Here, Kumar et al. present structures of GlyR bound to Δ9 -tetrahydrocannabinol (THC) using cryo-electron microscopy, providing insight into the therapeutic effects of cannabinoids.
- Arvind Kumar
- , Kayla Kindig
- & Sudha Chakrapani
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Article
| Open AccessThe molecular mechanism of snake short-chain α-neurotoxin binding to muscle-type nicotinic acetylcholine receptors
Bites by elapid snakes can result in life-threatening paralysis caused by α-neurotoxins blocking the neuromuscular nicotinic acetylcholine receptor. Here, the authors determine the cryo-EM structure of this receptor in complex with a short-chain α-neurotoxin.
- Mieke Nys
- , Eleftherios Zarkadas
- & Chris Ulens
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Article
| Open AccessCryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain
Here, Chi et al. report cryo-EM structures of the human Kv3.1a channel, revealing a unique arrangement of the cytoplasmic T1 domain, which allows the interactions with the C-terminal axonal targeting motif and key components of the gating machinery. These findings provide insights into the functional relevance of previously unknown interdomain interactions in Kv3 channels and may guide the design of new pharmaceutical drugs.
- Gamma Chi
- , Qiansheng Liang
- & Katharina L. Dürr