3,106 results match your criteria residues gating

The structure of MgtE in the absence of magnesium provides new insights into channel gating.

PLoS Biol 2021 Apr 27;19(4):e3001231. Epub 2021 Apr 27.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai, China.

MgtE is a Mg2+ channel conserved in organisms ranging from prokaryotes to eukaryotes, including humans, and plays an important role in Mg2+ homeostasis. The previously determined MgtE structures in the Mg2+-bound, closed-state, and structure-based functional analyses of MgtE revealed that the binding of Mg2+ ions to the MgtE cytoplasmic domain induces channel inactivation to maintain Mg2+ homeostasis. There are no structures of the transmembrane (TM) domain for MgtE in Mg2+-free conditions, and the pore-opening mechanism has thus remained unclear. Read More

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A conserved residue in the P2X4 receptor has a non-conserved function in ATP recognition.

J Biol Chem 2021 Apr 23:100655. Epub 2021 Apr 23.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China;. Electronic address:

Highly conserved amino acids are generally anticipated to have similar functions across a protein superfamily, including that of the P2X ion channels, which are gated by extracellular ATP. However, whether and how these functions are conserved becomes less clear when neighboring amino acids are not conserved. Here, we investigate one such case, focused on the highly conserved residue from P2X4, E118 (rat P2X4 numbering, rP2X4), a P2X subtype associated with human neuropathic pain. Read More

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Insights into the Molecular Inhibition of the Oncogenic Channel K10.1 by Globular Toxins.

J Chem Inf Model 2021 Apr 26. Epub 2021 Apr 26.

Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, México.

Inhibition of the expression of the human ether-à-go-go (hEAG1 or hK10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs. Read More

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Asymmetric CorA Gating Mechanism as Observed by Molecular Dynamics Simulations.

J Chem Inf Model 2021 Apr 22. Epub 2021 Apr 22.

Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, 9747AG Groningen, The Netherlands.

The CorA family of proteins plays a housekeeping role in the homeostasis of divalent metal ions in many bacteria and archaea as well as in mitochondria of eukaryotes, rendering it an important target to study the mechanisms of divalent transport and regulation across different life domains. Despite numerous studies, the mechanistic details of the channel gating and the transport of the metal ions are still not entirely understood. Here, we use all-atom and coarse-grained molecular dynamics simulations combined with experiments to investigate the influence of divalent cations on the function of CorA. Read More

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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).

Chem Rev 2021 Apr 22. Epub 2021 Apr 22.

Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Oho 1-1, Tsukuba, Ibaraki 305-0801, Japan.

The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. Over the last 10 years, more than a hundred different MFS transporter structures covering close to 40 members have provided an atomic framework for piecing together the molecular basis of their transport cycles. Read More

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Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains.

J Physiol 2021 Apr 20. Epub 2021 Apr 20.

Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

Key Points: Gap junctions formed by different connexins are expressed throughout the body and harbor unique channel properties that have not been fully defined mechanistically. Recent structural studies by Cryo-EM have produced high-resolution models of the related but functionally distinct lens connexins (Cx50 and Cx46) captured in a stable open state, opening the door for structure-function comparison. Here, we conducted comparative MD simulation and electrophysiology studies to dissect the isoform-specific differences in Cx46 and Cx50 intercellular channel function. Read More

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An arginine residue in the outer segment of hASIC1a TM1 affects both proton affinity and channel desensitization.

J Gen Physiol 2021 May;153(5)

Department of Basic Sciences, Tsinghua University School of Medicine, Beijing, China.

Acid-sensing ion channels (ASICs) respond to changes in pH in the central and peripheral nervous systems and participate in synaptic plasticity and pain perception. Understanding the proton-mediated gating mechanism remains elusive despite the of their structures in various conformational states. We report here that R64, an arginine located in the outer segment of the first transmembrane domain of all three isoforms of mammalian ASICs, markedly impacts the apparent proton affinity of activation and the degree of desensitization from the open and preopen states. Read More

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Probing the physiological roles of the extracellular loops of chitoporin from Vibrio campbellii.

Biophys J 2021 Apr 1. Epub 2021 Apr 1.

School of Biomolecular Science and Engineering (BSE), Vidyasirimedhi Institute of Science and Technology (VISTEC), Rayong, Thailand. Electronic address:

VhChiP, a sugar-specific porin found on the outer membrane of Vibrio campbellii, is responsible for the transport of chitooligosaccharides, allowing the bacterium to thrive in aquatic environments using chitin as a nutrient. We previously showed that VhChiP is composed of three identical subunits, each containing a 16-stranded β-barrel connected by eight extracellular loops and eight short periplasmic turns. This study is focused on the specific roles of three prominent extracellular loops of VhChiP-L2, L3, and L8. Read More

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Posttranslational regulation of CALHM1/3 channel: N-linked glycosylation and S-palmitoylation.

FASEB J 2021 May;35(5):e21527

Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Among calcium homeostasis modulator (CALHM) family members, CALHM1 and 3 together form a voltage-gated large-pore ion channel called CALHM1/3. CALHM1/3 plays an essential role in taste perception by mediating neurotransmitter release at channel synapses of taste bud cells. However, it is poorly understood how CALHM1/3 is regulated. Read More

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Time-resolved serial femtosecond crystallography reveals early structural changes in channelrhodopsin.

Elife 2021 03 23;10. Epub 2021 Mar 23.

RIKEN SPring-8 Center, Hyogo, Japan.

Channelrhodopsins (ChRs) are microbial light-gated ion channels utilized in optogenetics to control neural activity with light . Light absorption causes retinal chromophore isomerization and subsequent protein conformational changes visualized as optically distinguished intermediates, coupled with channel opening and closing. However, the detailed molecular events underlying channel gating remain unknown. Read More

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Gating of the capsaicin receptor TRPV1 by UVA-light and oxidants are mediated by distinct mechanisms.

Cell Calcium 2021 Mar 17;96:102391. Epub 2021 Mar 17.

Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625 Hannover, Germany. Electronic address:

Redox-sensitivity is a common property of several transient receptor potential (TRP) ion channels. Oxidants and UVA-light activate TRPV2 by oxidizing methionine pore residues which are conserved in the capsaicin-receptor TRPV1. However, the redox-sensitivity of TRPV1 is regarded to depend on intracellular cysteine residues. Read More

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Structure and activation mechanism of the human liver-type glutaminase GLS2.

Biochimie 2021 Mar 18;185:96-104. Epub 2021 Mar 18.

Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, Sao Paulo, Zip Code, 13083-970, Brazil; Sao Carlos Institute of Physics, University of Sao Paulo, Sao Carlos, SP, Zip Code, 13563-120, Brazil. Electronic address:

Cancer cells exhibit an altered metabolic phenotype, consuming higher levels of the amino acid glutamine. This metabolic reprogramming depends on increased mitochondrial glutaminase activity to convert glutamine to glutamate, an essential precursor for bioenergetic and biosynthetic processes in cells. Mammals encode the kidney-type (GLS) and liver-type (GLS2) glutaminase isozymes. Read More

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Channelrhodopsin C1C2: Photocycle kinetics and interactions near the central gate.

Biophys J 2021 May 9;120(9):1835-1845. Epub 2021 Mar 9.

Sandia National Laboratories, Albuquerque, New Mexico. Electronic address:

Channelrhodopsins (ChR) are light-sensitive cation channels used in optogenetics, a technique that applies light to control cells (e.g., neurons) that have been modified genetically to express those channels. Read More

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CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders.

Brain 2021 Mar 11. Epub 2021 Mar 11.

Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria.

T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Read More

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Hydrophobic Gate of Mechanosensitive Channel of Large Conductance in Lipid Bilayers Revealed by Solid-State NMR Spectroscopy.

J Phys Chem B 2021 03 8;125(10):2477-2490. Epub 2021 Mar 8.

Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology and the Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430074, China.

The bacterial mechanosensitive channel of large conductance (MscL) functions as a pressure-relief safety valve to prevent cells from lysing during sudden hypo-osmotic shock. The hydrophobic gate of MscL in the closed state forms a barrier to the permeation of ions and water molecules and can be switched to the open state for releasing solutions and ions. Currently, the gate-constituting residues and the functional role of these residues in the hydrophobic gate of MscL remain elusive and controversial. Read More

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Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel.

J Gen Physiol 2021 Apr;153(4)

Science for Life Laboratory, Department of Applied Physics, KTH Royal Institute of Technology, Stockholm, Sweden.

Voltage-gated potassium (KV) channels can be opened by negatively charged resin acids and their derivatives. These resin acids have been proposed to attract the positively charged voltage-sensor helix (S4) toward the extracellular side of the membrane by binding to a pocket located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. By contrast to this proposed mechanism, neutralization of the top gating charge of the Shaker KV channel increased resin-acid-induced opening, suggesting other mechanisms and sites of action. Read More

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Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.

Front Cell Dev Biol 2021 11;9:635705. Epub 2021 Feb 11.

JKU Life Science Center, Institute of Biophysics, Johannes Kepler University Linz, Linz, Austria.

STIM1-mediated activation of calcium selective Orai channels is fundamental for life. The three Orai channel isoforms, Orai1-3, together with their multiple ways of interplay, ensure their highly versatile role in a variety of cellular functions and tissues in both, health and disease. While all three isoforms are activated in a store-operated manner by STIM1, they differ in diverse biophysical and structural properties. Read More

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February 2021

A glycan gate controls opening of the SARS-CoV-2 spike protein.

bioRxiv 2021 Feb 16. Epub 2021 Feb 16.

SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded (down) to an exposed (up) state in order to bind the human ACE2 receptor and infect cells. While snapshots of the up and down states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 200 μs of weighted ensemble (WE) simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD opening pathways. Read More

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February 2021

Deciphering the Mechanism of Inhibition of SERCA1a by Sarcolipin Using Molecular Simulations.

Front Mol Biosci 2020 4;7:606254. Epub 2021 Feb 4.

CNRS UMR9187 / INSERM U1196, Institut Curie, PSL Research University, Université Paris-Saclay, Orsay, France.

SERCA1a is an ATPase calcium pump that transports Ca from the cytoplasm to the sarco/endoplasmic reticulum lumen. Sarcolipin (SLN), a transmembrane peptide, regulates the activity of SERCA1a by decreasing its Ca transport rate, but its mechanism of action is still not well-understood. To decipher this mechanism, we have performed normal mode analysis in the all-atom model, with the SERCA1a-SLN complex, or the isolated SERCA1a, embedded in an explicit membrane. Read More

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February 2021

The Underlying Mechanism of Modulation of Transient Receptor Potential Melastatin 3 by protons.

Front Pharmacol 2021 2;12:632711. Epub 2021 Feb 2.

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United States.

Transient receptor potential melastatin 3 channel (TRPM3) is a calcium-permeable nonselective cation channel that plays an important role in modulating glucose homeostasis in the pancreatic beta cells. However, how TRPM3 is regulated under physiological and pathological conditions is poorly understood. In this study, we found that both intracellular and extracellular protons block TRPM3 through its binding sites in the pore region. Read More

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February 2021

HCN Channel Phosphorylation Sites Mapped by Mass Spectrometry in Human Epilepsy Patients and in an Animal Model of Temporal Lobe Epilepsy.

Neuroscience 2021 04 9;460:13-30. Epub 2021 Feb 9.

Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United States. Electronic address:

Because hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels modulate the excitability of cortical and hippocampal principal neurons, these channels play a key role in the hyperexcitability that occurs during the development of epilepsy after a brain insult, or epileptogenesis. In epileptic rats generated by pilocarpine-induced status epilepticus, HCN channel activity is downregulated by two main mechanisms: a hyperpolarizing shift in gating and a decrease in amplitude of the current mediated by HCN channels, I. Because these mechanisms are modulated by various phosphorylation signaling pathways, we hypothesized that phosphorylation changes occur at individual HCN channel amino acid residues (phosphosites) during epileptogenesis. Read More

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Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.

Commun Biol 2021 Feb 9;4(1):174. Epub 2021 Feb 9.

Neuroscience Discovery, Janssen Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA, 92121, USA.

Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Read More

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February 2021

Gating the pore of the calcium-activated chloride channel TMEM16A.

Nat Commun 2021 02 4;12(1):785. Epub 2021 Feb 4.

Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.

The binding of cytoplasmic Ca to the anion-selective channel TMEM16A triggers a conformational change around its binding site that is coupled to the release of a gate at the constricted neck of an hourglass-shaped pore. By combining mutagenesis, electrophysiology, and cryo-electron microscopy, we identified three hydrophobic residues at the intracellular entrance of the neck as constituents of this gate. Mutation of each of these residues increases the potency of Ca and results in pronounced basal activity. Read More

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February 2021

Conformational heterogeneity of the voltage sensor loop of KvAP in micelles and membranes: A fluorescence approach.

Biochim Biophys Acta Biomembr 2021 May 30;1863(5):183568. Epub 2021 Jan 30.

Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, Homi Bhabha National Institute, 1/AF Bidhannagar, Kolkata, India. Electronic address:

KvAP is a tetrameric voltage-gated potassium channel that is composed of a pore domain and a voltage-sensing domain (VSD). The VSD is crucial for sensing transmembrane potential and gating. At 0 mV, the VSD adopts an activated conformation in both n-octylglucoside (OG) micelles and phospholipid membranes. Read More

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Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human Ca3.3 Channel.

ACS Chem Neurosci 2021 02 28;12(4):651-659. Epub 2021 Jan 28.

School of Chemical Sciences, Meritorious Autonomous University of Puebla (BUAP), University City, Puebla 72570, Mexico.

Regulation of cellular excitability and oscillatory behavior of resting membrane potential in nerve cells are largely mediated by the low-voltage activated T-type calcium channels. This calcium channel family is constituted by three isoforms, namely, Ca3.1, Ca3. Read More

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February 2021

A conserved arginine with non-conserved function is a key determinant of agonist selectivity in α7 nicotinic ACh receptors.

Br J Pharmacol 2021 Apr 27;178(7):1651-1668. Epub 2021 Feb 27.

School of Biochemistry, University of Bristol, Bristol, UK.

Background And Purpose: The α7 and α4β2* ("*" denotes possibly assembly with another subunit) nicotinic acetylcholine receptors (nAChRs) are the most abundant nAChRs in the mammalian brain. These receptors are the most targeted nAChRs in drug discovery programmes for brain disorders. However, the development of subtype-specific agonists remains challenging due to the high degree of sequence homology and conservation of function in nAChRs. Read More

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α Subunit Histidine 55 at the Interface between Extracellular and Transmembrane Domains Affects Preactivation and Desensitization of the GABA Receptor.

ACS Chem Neurosci 2021 02 20;12(3):562-572. Epub 2021 Jan 20.

Department of Biophysics and Neuroscience, Wroclaw Medical University, Chalubinskiego 3a, Wroclaw, Dolnoślaskie 50-368, Poland.

The GABA receptor is a member of the Cys-loop family and plays a crucial role in the adult mammalian brain inhibition. Although the static structure of this receptor is emerging, the molecular mechanisms underlying its conformational transitions remain elusive. It is known that in the Cys-loop receptors, the interface between extracellular and transmembrane domains plays a key role in transmitting the "activation wave" down to the channel gate in the pore. Read More

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February 2021

Plant aquaporins alleviate drought tolerance in plants by modulating cellular biochemistry, root-architecture, and photosynthesis.

Physiol Plant 2021 Jan 9. Epub 2021 Jan 9.

Division of Applied Phycology and Biotechnology, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar, India.

Water is a vital resource for plants to grow, thrive, and complete their life cycle. In recent years, drastic changes in the climate, especially drought frequency and severity, have increased, which reduces agricultural productivity worldwide. Aquaporins are membrane channels belonging to the major intrinsic protein superfamily, which play an essential role in cellular water and osmotic homeostasis of plants under both control and water deficit conditions. Read More

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January 2021

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

BMC Mol Cell Biol 2021 Jan 7;22(1). Epub 2021 Jan 7.

Graduate School of Pharmaceutical Sciences, Keio University, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.

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. Read More

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January 2021

Molecular simulation of the Kv7.4[ΔS269] mutant channel reveals that ion conduction in the cavity is perturbed due to hydrophobic gating.

Biochem Biophys Rep 2021 Mar 16;25:100879. Epub 2020 Dec 16.

School of Engineering, RMIT University, Melbourne, Victoria, 3001, Australia.

Mutations in the voltage-gated potassium channel Kv7.4 (encoded as KCNQ4) lead to the early onset of non-syndromic hearing loss, which is significant during language acquisition. The deletion of the S269 pore residue (genetic Δ mutation) in Kv7. Read More

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