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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

0

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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.

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

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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