scholarly journals Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

Cell ◽  
2019 ◽  
Vol 176 (4) ◽  
pp. 702-715.e14 ◽  
Author(s):  
Hui Xu ◽  
Tianbo Li ◽  
Alexis Rohou ◽  
Christopher P. Arthur ◽  
Foteini Tzakoniati ◽  
...  
Keyword(s):  
Structural Basis ◽  
Spider Toxin ◽  
Gating Modifier

scholarly journals Structural Basis of Nav1.7 Inhibition by a Gating-Modifier Spider Toxin

Cell ◽  
2019 ◽  
Vol 176 (5) ◽  
pp. 1238-1239 ◽  
Author(s):  
Hui Xu ◽  
Tianbo Li ◽  
Alexis Rohou ◽  
Christopher P. Arthur ◽  
Foteini Tzakoniati ◽  
...  
Keyword(s):  
Structural Basis ◽  
Spider Toxin ◽  
Gating Modifier

scholarly journals Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin

2020 ◽  
Author(s):  
Daohua Jiang ◽  
Lige Tonggu ◽  
Tamer M. Gamal El-Din ◽  
Richard Banh ◽  
Régis Pomès ◽  
...  
Keyword(s):  
Ion Pairs ◽  
Voltage Sensor ◽  
Structural Basis ◽  
Fast Inactivation ◽  
Toxin Binding ◽  
Cardiac Sodium Channel ◽  
Activated State ◽  
Nav Channels ◽  
Gating Modifier ◽  
Voltage Sensing Domain

AbstractVoltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50=11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

scholarly journals Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Kazuki Matsumura ◽  
Takushi Shimomura ◽  
Yoshihiro Kubo ◽  
Takayuki Oka ◽  
Naohiro Kobayashi ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Resting State ◽  
Mutational Analysis ◽  
Functional Characterization ◽  
Structural Basis ◽  
Anthopleura Elegantissima ◽  
Gating Modifier ◽  
Peptide Toxin ◽  
Key Residues ◽  
Voltage Sensing Domain

Abstract Background Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels.

scholarly journals Structural basis for the modulation of voltage-gated sodium channels by animal toxins

Science ◽  
2018 ◽  
Vol 362 (6412) ◽  
pp. eaau2596 ◽  
Author(s):  
Huaizong Shen ◽  
Zhangqiang Li ◽  
Yan Jiang ◽  
Xiaojing Pan ◽  
Jianping Wu ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Structural Basis ◽  
Shellfish Poisoning ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Puffer Fish ◽  
Gating Modifier ◽  
Extracellular Side ◽  
Fish And Shellfish ◽  
Shed Light

Animal toxins that modulate the activity of voltage-gated sodium (Nav) channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Navchannel NavPaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSDIIand the pore of NavPaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na+access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Navchannel drugs.

scholarly journals Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daohua Jiang ◽  
Lige Tonggu ◽  
Tamer M. Gamal El-Din ◽  
Richard Banh ◽  
Régis Pomès ◽  
...  
Keyword(s):  
Ion Pairs ◽  
Voltage Sensor ◽  
Structural Basis ◽  
Fast Inactivation ◽  
Excitable Cells ◽  
Toxin Binding ◽  
Cardiac Sodium Channel ◽  
Activated State ◽  
Gating Modifier ◽  
Voltage Sensing Domain

AbstractVoltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50 = 11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na+ permeation, revealing why LqhIII slows inactivation of NaV channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of NaV channels.

scholarly journals Structural basis for the inhibition of voltage-dependent K+ channel by gating modifier toxin

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Shin-ichiro Ozawa ◽  
Tomomi Kimura ◽  
Tomohiro Nozaki ◽  
Hitomi Harada ◽  
Ichio Shimada ◽  
...  
Keyword(s):  
Structural Basis ◽  
K Channel ◽  
Voltage Dependent ◽  
Gating Modifier

scholarly journals Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

2020 ◽  
Author(s):  
Kazuki Matsumura ◽  
Takushi Shimomura ◽  
Yoshihiro Kubo ◽  
Takayuki Oka ◽  
Naohiro Kobayashi ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Resting State ◽  
Mutational Analysis ◽  
Functional Characterization ◽  
Structural Basis ◽  
Related Gene ◽  
Wild Type ◽  
Hydrophobic Residues ◽  
Gating Modifier ◽  
Voltage Sensing Domain

AbstractHuman ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. Although it is known that APETx1 inhibits hERG by stabilizing the resting state, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Here, we prepared a recombinant APETx1, which is structurally and functionally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, in addition to a previously reported acidic hERG residue, play key roles in the inhibition of hERG by APETx1. Docking models of the APETx1-VSD complex that satisfy the results of mutational analysis suggest a molecular recognition mode between APETx1 and the resting state of hERG; this would provide a structural basis for designing ligands that control hERG function by binding to the VSD.

scholarly journals Spider toxin inhibits gating pore currents underlying periodic paralysis

2018 ◽  
Vol 115 (17) ◽  
pp. 4495-4500 ◽  
Author(s):  
Roope Männikkö ◽  
Zakhar O. Shenkarev ◽  
Michael G. Thor ◽  
Antonina A. Berkut ◽  
Mikhail Yu Myshkin ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Specific Binding ◽  
Periodic Paralysis ◽  
Extracellular Loop ◽  
Nmr Studies ◽  
Spider Toxin ◽  
Electrostatic And Hydrophobic Interactions ◽  
Gating Modifier ◽  
Crab Spider

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3–S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.

Organization of tight junctions in the choroid plexus epithelium

1978 ◽  
Vol 36 (2) ◽  
pp. 336-337
Author(s):  
B. Van Deurs ◽  
J. K. Koehler
Keyword(s):  
Choroid Plexus ◽  
Present Report ◽  
Freeze Fracture ◽  
Barrier Properties ◽  
Cell Junctions ◽  
Structural Basis ◽  
Apical Surface ◽  
Choroid Plexus Epithelium ◽  
Solid Nitrogen ◽  
Special Composition

The choroid plexus epithelium constitutes a blood-cerebrospinal fluid (CSF) barrier, and is involved in regulation of the special composition of the CSF. The epithelium is provided with an ouabain-sensitive Na/K-pump located at the apical surface, actively pumping ions into the CSF. The choroid plexus epithelium has been described as “leaky” with a low transepithelial resistance, and a passive transepithelial flux following a paracellular route (intercellular spaces and cell junctions) also takes place. The present report describes the structural basis for these “barrier” properties of the choroid plexus epithelium as revealed by freeze fracture.Choroid plexus from the lateral, third and fourth ventricles of rats were used. The tissue was fixed in glutaraldehyde and stored in 30% glycerol. Freezing was performed either in liquid nitrogen-cooled Freon 22, or directly in a mixture of liquid and solid nitrogen prepared in a special vacuum chamber. The latter method was always used, and considered necessary, when preparations of complementary (double) replicas were made.

High resolution spot scan imaging of frozen, hydrated actin bundles with 400kV electrons

1992 ◽  
Vol 50 (1) ◽  
pp. 512-513
Author(s):  
J. Jakana ◽  
M.F. Schmid ◽  
P. Matsudaira ◽  
W. Chiu
Keyword(s):  
High Resolution ◽  
Binding Proteins ◽  
Actin Binding ◽  
Eukaryotic Cells ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Actin Bundle ◽  
Actin Bundles ◽  
3 Dimensional ◽  
Macromolecular Assembly

Actin is a protein found in all eukaryotic cells. In its polymerized form, the cells use it for motility, cytokinesis and for cytoskeletal support. An example of this latter class is the actin bundle in the acrosomal process from the Limulus sperm. The different functions actin performs seem to arise from its interaction with the actin binding proteins. A 3-dimensional structure of this macromolecular assembly is essential to provide a structural basis for understanding this interaction in relationship to its development and functions.

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