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channelopathies SIGNED

Type 1 reyanodine receptor Structure and regulation by post-translational modifications and small molecules.

Total Cost €

0

EC-Contrib. €

0

Partnership

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 channelopathies project word cloud

Explore the words cloud of the channelopathies project. It provides you a very rough idea of what is the project "channelopathies" about.

muscles    electron    classification    caffeine    drug    adrenergic    forming    model    ec    post    ion    cryo    cardiac    cytosolic    calcium    intracellular    small    endoplasmic    particles    gating    release    broad    coupling    ray    basis    placing    channels    sarcoplasmic    drugs    contraction    malignant    reticuli    stores    native    notably    excitation    signaling    molecules    structure    atp    em    sites    structural    pore    activated    dystrophy    ryr2    rycals    microscopy    stimulation    ryr    closed    channel    fragments    protomers    completing    aring    ryrs    receptor    regulation    transmembrane    tertiary    amongst    revealed    folds    potent    resolution    binding    domains    conformations    translational    crystallography    ryr1    mechanism    ryanodine    muscular    comprised    identical    skeletal    length    data    unprecedented    modifications    regulated    cell    multiple    safer    dantrolene    kda    mammalian    hyperthermia    picture    details    full    types    atomic    ligands    dynamic    unambiguously    565   

Project "channelopathies" data sheet

The following table provides information about the project.

Coordinator
BEN-GURION UNIVERSITY OF THE NEGEV 

Organization address
address: .
city: BEER SHEVA
postcode: 84105
website: www.bgu.ac.il

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Israel [IL]
 Project website http://lifeserv.bgu.ac.il/wp/cryoem/
 Total cost 182˙509 €
 EC max contribution 182˙509 € (100%)
 Programme 1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility)
 Code Call H2020-MSCA-IF-2015
 Funding Scheme MSCA-IF-EF-RI
 Starting year 2016
 Duration (year-month-day) from 2016-03-01   to  2018-02-28

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    BEN-GURION UNIVERSITY OF THE NEGEV IL (BEER SHEVA) coordinator 182˙509.00

Map

 Project objective

This proposal is aiming at understanding the structural basis of the type 1 ryanodine receptor (RyR1) regulation by post-translational modifications and by small molecules. RyR1 is present on the sarcoplasmic and endoplasmic reticuli of many mammalian cell types, most notably, in skeletal muscles. RyR channels are required for calcium release from intracellular stores, a process essential for excitation-contraction (EC) coupling in skeletal (RyR1) and cardiac (RyR2) muscles. They are amongst the largest ion channels, comprised of the four identical ~565 kDa channel-forming protomers. RyRs channel activity is regulated by post-translational modifications through multiple signaling pathways including adrenergic stimulation. We have obtained a 4.3 Å resolution cryo-electron microscopy (Cryo-EM) structure of RyR1 in the closed state and a 3.6 Å structure in an activated state. An atomic model was built, defining the transmembrane pore, placing all cytosolic domains as tertiary folds and unambiguously identifying small ligands including calcium, ATP, caffeine and the ryanodine in unprecedented details. In both data sets obtained, 3-D classification of particles revealed multiple distinct conformations providing a broad detailed picture of the dynamic process of RyR1 gating. Here, I aim at improving and completing the atomic model of RyR1 and at determining the structural basis for RyR1 regulation by post-translational modifications and by small molecules. I will use X-ray crystallography to determine the high-resolution structure of the full length RyR1 as well as small fragments including the transmembrane pore and drug binding sites. Cryo–EM and 3-D classification will be used to identify structural changes induced by post-translational modifications and by native ligands and drugs binding. The mechanism of drugs targeting RyRs such as dantrolene and rycals can lead to structure-based design of more potent/safer drugs for malignant hyperthermia and muscular dystrophy.

 Publications

year authors and title journal last update
List of publications.
2017 Ran Zalk, Andrew R. Marks
Ca 2+ Release Channels Join the ‘Resolution Revolution’
published pages: 543-555, ISSN: 0968-0004, DOI: 10.1016/j.tibs.2017.04.005
Trends in Biochemical Sciences 42/7 2019-06-13

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