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Structure paper

TitleMolecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 116, Issue 51, Page 25575-25582, Year 2019
Publish dateDec 17, 2019
AuthorsXimin Chi / Deshun Gong / Kang Ren / Gewei Zhou / Gaoxingyu Huang / Jianlin Lei / Qiang Zhou / Nieng Yan /
PubMed AbstractThe type 2 ryanodine receptor (RyR2) is responsible for releasing Ca from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report 4 cryo-electron ...The type 2 ryanodine receptor (RyR2) is responsible for releasing Ca from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report 4 cryo-electron microscopy (cryo-EM) structures of porcine RyR2 bound to distinct modulators that, together with our published structures, provide mechanistic insight into RyR2 regulation. Ca alone induces a contraction of the central domain that facilitates the dilation of the S6 bundle but is insufficient to open the pore. The small-molecule agonist PCB95 helps Ca to overcome the barrier for opening. FKBP12.6 induces a relaxation of the central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state even in the presence of Ca and PCB95. Although the channel is open when PCB95 is replaced by caffeine and adenosine 5'-triphosphate (ATP), neither of the modulators alone can sufficiently counter the antagonistic effect to open the channel. Our study marks an important step toward mechanistic understanding of the sophisticated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.
External linksProc Natl Acad Sci U S A / PubMed:31792195 / PubMed Central
MethodsEM (single particle)
Resolution4.5 - 6.1 Å
Structure data

9823

6jg3

EMDB-9823: Structure of RyR2 (Ca2+ alone dataset)
PDB-6jg3: Cryo-EM structure of RyR2 (Ca2+ alone dataset)
Method: EM (single particle) / Resolution: 6.1 Å

9824

6jgz

EMDB-9824, PDB-6jgz:
Structure of RyR2 (F/P/Ca2+ dataset)
Method: EM (single particle) / Resolution: 4.6 Å

9825

6jh6

EMDB-9825, PDB-6jh6:
Structure of RyR2 (F/A/Ca2+ dataset)
Method: EM (single particle) / Resolution: 4.8 Å

9826

6jhn

EMDB-9826, PDB-6jhn:
Structure of RyR2 (F/C/Ca2+ dataset)
Method: EM (single particle) / Resolution: 4.5 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-CA:
Unknown entry

ChemComp-CFF:
CAFFEINE / medication*YM / Caffeine (data page)

Source
  • sus scrofa (pig)
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / cryo-EM

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