8,109 results match your criteria binding gating

Pollen PCP-B peptides unlock a stigma peptide-receptor kinase gating mechanism for pollination.

Science 2021 04;372(6538):171-175

School of Life Sciences, East China Normal University, Shanghai, China.

Sexual reproduction in angiosperms relies on precise communications between the pollen and pistil. The molecular mechanisms underlying these communications remain elusive. We established that in , a stigmatic gatekeeper, the ANJEA-FERONIA (ANJ-FER) receptor kinase complex, perceives the RAPID ALKALINIZATION FACTOR peptides RALF23 and RALF33 to induce reactive oxygen species (ROS) production in the stigma papillae, whereas pollination reduces stigmatic ROS, allowing pollen hydration. Read More

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

A Aunkham W Suginta

Biophys J 2021 Apr 1. Epub 2021 Apr 1.

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 nutrient. We previously showed that VhChiP is composed of three identical subunits, each containing a 16-stranded β-barrel connected by 8 extracellular loops and 8 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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Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel Na1.7 Can Be Predicted Using Accurate Free-Energy Calculations.

Toxins (Basel) 2021 Mar 7;13(3). Epub 2021 Mar 7.

Schrӧdinger, Inc., 120 West 45th St., New York, NY 10036, USA.

Gating modifier toxins (GMTs) isolated from venomous organisms such as Protoxin-II (ProTx-II) and Huwentoxin-IV (HwTx-IV) that inhibit the voltage-gated sodium channel Na1.7 by binding to its voltage-sensing domain II (VSDII) have been extensively investigated as non-opioid analgesics. However, reliably predicting how a mutation to a GMT will affect its potency for Na1. Read More

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Signal transduction through Cys-loop receptors is mediated by the nonspecific bumping of closely apposed domains.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801;

One of the most fundamental questions in the field of Cys-loop receptors (pentameric ligand-gated ion channels, pLGICs) is how the affinity for neurotransmitters and the conductive/nonconductive state of the transmembrane pore are correlated despite the ∼60-Å distance between the corresponding domains. Proposed mechanisms differ, but they all converge into the idea that interactions between wild-type side chains across the extracellular-transmembrane-domain (ECD-TMD) interface are crucial for this phenomenon. Indeed, the successful design of fully functional chimeras that combine intact ECD and TMD modules from different wild-type pLGICs has commonly been ascribed to the residual conservation of sequence that exists at the level of the interfacial loops even between evolutionarily distant parent channels. Read More

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Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time.

J Vis Exp 2021 Mar 11(169). Epub 2021 Mar 11.

Department of Physiology, Anatomy and Genetics, University of Oxford; Department of Chemistry and Neuroscience Program, Trinity College;

We have developed a method to measure binding of adenine nucleotides to intact, functional transmembrane receptors in a cellular or membrane environment. This method combines expression of proteins tagged with the fluorescent non-canonical amino acid ANAP, and FRET between ANAP and fluorescent (trinitrophenyl) nucleotide derivatives. We present examples of nucleotide binding to ANAP-tagged KATP ion channels measured in unroofed plasma membranes and excised, inside-out membrane patches under voltage clamp. Read More

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ADP-Ribosylation Regulates the Signaling Function of IFN-γ.

Front Immunol 2021 8;12:642545. Epub 2021 Mar 8.

Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Murine T cells express the GPI-anchored ADP-ribosyltransferase 2.2 (ARTC2.2) on the cell surface. Read More

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The Groovy TMEM16 Family: Molecular Mechanisms of Lipid Scrambling and Ion Conduction.

J Mol Biol 2021 Mar 16:166941. Epub 2021 Mar 16.

Structural Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, Netherlands. Electronic address:

The TMEM16 family of membrane proteins displays a remarkable functional dichotomy - while some family members function as Ca-activated anion channels, the majority of characterized TMEM16 homologs are Ca-activated lipid scramblases, which catalyze the exchange of phospholipids between the two membrane leaflets. Furthermore, some TMEM16 scramblases can also function as channels. Due to their involvement in important physiological processes, the family has been actively studied ever since their molecular identity was unraveled. Read More

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Predicting lipid and ligand binding sites in TRPV1 channel by molecular dynamics simulation and machine learning.

Proteins 2021 Mar 19. Epub 2021 Mar 19.

Department of Physics, State University of New York at Buffalo, Buffalo, New York, USA.

As a key cellular sensor, the TRPV1 channel undergoes a gating transition from a closed state to an open state in response to many physical and chemical stimuli. This transition is regulated by small-molecule ligands including lipids and various agonists/antagonists, but the underlying molecular mechanisms remain obscure. Thanks to recent revolution in cryo-electron microscopy, a growing list of new structures of TRPV1 and other TRPV channels have been solved in complex with various ligands including lipids. Read More

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Physical and Chemical Interplay Between the Membrane and a Prototypical Potassium Channel Reconstituted on a Lipid Bilayer Platform.

Front Mol Neurosci 2021 26;14:634121. Epub 2021 Feb 26.

Biomedical Imaging Research Center, University of Fukui, Fukui, Japan.

Once membrane potential changes or ligand binding activates the ion channel, the activity of the channel is finely modulated by the fluctuating membrane environment, involving local lipid composition and membrane tension. In the age of post-structural biology, the factors in the membrane that affect the ion channel function and how they affect it are a central concern among ion channel researchers. This review presents our strategies for elucidating the molecular mechanism of membrane effects on ion channel activity. Read More

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February 2021

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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Conformational Ensemble of AdoCbl Riboswitch Provides Stable Structural Elements for Conformation Selection and Population Shift in Cobalamin Recognition.

J Phys Chem B 2021 03 8;125(10):2589-2596. Epub 2021 Mar 8.

Protein-Nucleic Acid Interaction Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.

Cobalamin riboswitch is a cis-regulatory element widely found in the 5'-UTRs of the vitamin B12-associated genes in bacteria, resulting in modulation and production of a particular protein. Thermoanaerobacter tengcongensis () AdoCbl riboswitches are the largest of the known riboswitches with 210 nucleotides, partially due to its long peripheral P6-extension, which enable high affinity of AdoCbl. Two structural elements, T-loop/T-looplike motif and kissing loop are key to the global folding of the RNA. Read More

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Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.

Molecules 2021 Feb 13;26(4). Epub 2021 Feb 13.

Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México, Campus Juriquilla, Boulevard Juriquilla 3001, Juriquilla, Querétaro 76230, Mexico.

Several antidepressants inhibit nicotinic acetylcholine receptors (nAChRs) in a non-competitive and voltage-dependent fashion. Here, we asked whether antidepressants with a different structure and pharmacological profile modulate the rat α7 nAChR through a similar mechanism by interacting within the ion-channel. We applied electrophysiological (recording of the ion current elicited by choline, I, which activates α7 nAChRs from rat CA1 hippocampal interneurons) and in silico approaches (homology modeling of the rat α7 nAChR, molecular docking, molecular dynamics simulations, and binding free energy calculations). Read More

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February 2021

Lipid regulation of hERG1 channel function.

Nat Commun 2021 03 3;12(1):1409. Epub 2021 Mar 3.

Centre for Molecular Simulation and Department of Biological Sciences, 507 Campus Drive, University of Calgary, Calgary, AB, Canada.

The lipid regulation of mammalian ion channel function has emerged as a fundamental mechanism in the control of electrical signalling and transport specificity in various cell types. In this work, we combine molecular dynamics simulations, mutagenesis, and electrophysiology to provide mechanistic insights into how lipophilic molecules (ceramide-sphingolipid probe) alter gating kinetics and K currents of hERG1. We show that the sphingolipid probe induced a significant left shift of activation voltage, faster deactivation rates, and current blockade comparable to traditional hERG1 blockers. Read More

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Structural mechanisms of gating and selectivity of human rod CNGA1 channel.

Neuron 2021 Feb 19. Epub 2021 Feb 19.

Howard Hughes Medical Institute and Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

Mammalian cyclic nucleotide-gated (CNG) channels play an essential role in the signal transduction of the visual and olfactory sensory systems. Here we reveal the structural mechanism of ligand gating in human rod CNGA1 channel by determining its cryo-EM structures in both the apo closed and cGMP-bound open states. Distinct from most other members of voltage-gated tetrameric cation channels, CNGA1 forms a central channel gate in the middle of the membrane, occluding the central cavity. Read More

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February 2021

Specific PIP binding promotes calcium activation of TMEM16A chloride channels.

Commun Biol 2021 Feb 26;4(1):259. Epub 2021 Feb 26.

Department of Chemistry, University of Massachusetts, Amherst, MA, USA.

TMEM16A is a widely expressed Ca-activated Cl channel that regulates crucial physiological functions including fluid secretion, neuronal excitability, and smooth muscle contraction. There is a critical need to understand the molecular mechanisms of TMEM16A gating and regulation. However, high-resolution TMEM16A structures have failed to reveal an activated state with an unobstructed permeation pathway even with saturating Ca. 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

Tuning Protein Discrimination Through Altering the Sampling Interface Formed between the Analyte and the OmpG Nanopore.

ACS Sens 2021 03 18;6(3):1286-1294. Epub 2021 Feb 18.

Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, Massachusetts 01003, United States.

Nanopore sensors capable of distinguishing homologous protein analytes are highly desirable tools for proteomics research and disease diagnostics. Recently, an engineered outer membrane protein G (OmpG) nanopore with a high-affinity ligand attached to a gating loop 6 showed specificity for distinguishing homologous proteins in complex mixtures. Here, we report the development of OmpG nanopores with the other six loops used as the anchoring point to host an affinity ligand for protein sensing. Read More

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Mechanism of gating and partial agonist action in the glycine receptor.

Cell 2021 Feb 9;184(4):957-968.e21. Epub 2021 Feb 9.

Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address:

Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Read More

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February 2021

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

Caffeine-Operated Synthetic Modules for Chemogenetic Control of Protein Activities by Life Style.

Adv Sci (Weinh) 2021 Feb 13;8(3):2002148. Epub 2020 Dec 13.

Center for Translational Cancer Research Institute of Biosciences and Technology Texas A&M University Houston TX 77030 USA.

A genetically encoded caffeine-operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti-caffeine nanobody via cell-based high-throughput screening, permits caffeine-inducible gating of calcium channels, tumor killing via necroptosis, growth factors-independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody-mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS-CoV-2) spike protein. Read More

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February 2021

Mechanism of pore opening in the calcium-activated chloride channel TMEM16A.

Nat Commun 2021 02 4;12(1):786. Epub 2021 Feb 4.

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

The anion channel TMEM16A is activated by intracellular Ca in a highly cooperative process. By combining electrophysiology and autocorrelation analysis, we investigated the mechanism of channel activation and the concurrent rearrangement of the gate in the narrow part of the pore. Features in the fluctuation characteristics of steady-state current indicate the sampling of intermediate conformations that are successively occupied during gating. 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

NMDA Receptors Singled out for Delayed Activation.

Neuron 2021 02;109(3):395-397

Humboldt University Berlin, Leibniz-Institut für Molekulare Pharmakologie & Cluster of Excellence NeuroCure, Robert-Rössle-Str. 10, 13125 Berlin, Germany. Electronic address:

In this issue of Neuron, Amin et al. (2021) recorded single NMDA receptors in synaptic-like conditions to reveal how unreliable coupling between agonist binding and channel opening depends on structured linkers. After neurotransmitter binding, a complicated molecular "discussion" ensues, dividing fast synaptic events from delayed openings and failures. Read More

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February 2021

SARS-CoV-2 recruits a haem metabolite to evade antibody immunity.

medRxiv 2021 Jan 26. Epub 2021 Jan 26.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). Read More

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January 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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Bio-adhesive Nanoporous Module: Toward Autonomous Gating.

Angew Chem Int Ed Engl 2021 Apr 3;60(16):8932-8937. Epub 2021 Mar 3.

Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.

Here we report a bio-adhesive porous organic module ( COF) composed of hexagonally packed 1D nanopores based on a covalent organic framework. The nanopores are densely decorated with guanidinium ion (Gu ) pendants capable of forming salt bridges with oxyanionic species. COF strongly adheres to biopolymers through multivalent salt-bridging interactions with their ubiquitous oxyanionic species. Read More

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Serotonin 5-HT receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant.

Psychopharmacology (Berl) 2021 Apr 29;238(4):1111-1120. Epub 2021 Jan 29.

Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Dr., Unit 78, New York, NY, 10032, USA.

Rationale: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT receptor is associated with repetitive behaviors seen in both disorders. 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