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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.

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

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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