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

Información del proyecto

channelopathies

Identificador del acuerdo de subvención: 708572

DOI

10.3030/708572

Proyecto cerrado

Fecha de la firma de la CE 22 Febrero 2016

Fecha de inicio 1 Marzo 2016

Fecha de finalización 28 Febrero 2018

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 182 509,20

Aportación de la UE

€ 182 509,20

Coordinado por

BEN-GURION UNIVERSITY OF THE NEGEV
Israel

Objetivo

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.

Ámbito científico (EuroSciVoc)

• ciencias médicas y de la salud › medicina clínica › cardiología › enfermedad cardiovascular › arritmia cardíaca
• ciencias médicas y de la salud › medicina básica › neurología › distrofia muscular
• ciencias naturales › ciencias de la tierra y ciencias ambientales conexas › geología › mineralogía › cristalografía
• ciencias naturales › ciencias químicas › química inorgánica › metales alcalinotérreos
• ciencias naturales › ciencias biológicas › genética › mutación

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF)
  

Régimen de financiación

MSCA-IF-EF-RI - RI – Reintegration panel

Convocatoria de propuestas

H2020-MSCA-IF-2015

Coordinador

BEN-GURION UNIVERSITY OF THE NEGEV

• Aportación neta de la UEn: € 182 509,20
• Dirección: . ; 84105 Beer Sheva ; Israel
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 182 509,20