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TitleAllosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives.
Journal, issue, pagesStructure, Vol. 31, Issue 7, Page 790-800.e4, Year 2023
Publish dateJul 6, 2023
AuthorsSpencer Cholak / James W Saville / Xing Zhu / Alison M Berezuk / Katharine S Tuttle / Omid Haji-Ghassemi / Francisco J Alvarado / Filip Van Petegem / Sriram Subramaniam /
PubMed AbstractThe coordinated release of Ca from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the ...The coordinated release of Ca from the sarcoplasmic reticulum (SR) is critical for excitation-contraction coupling. This release is facilitated by ryanodine receptors (RyRs) that are embedded in the SR membrane. In skeletal muscle, activity of RyR1 is regulated by metabolites such as ATP, which upon binding increase channel open probability (P). To obtain structural insights into the mechanism of RyR1 priming by ATP, we determined several cryo-EM structures of RyR1 bound individually to ATP-γ-S, ADP, AMP, adenosine, adenine, and cAMP. We demonstrate that adenine and adenosine bind RyR1, but AMP is the smallest ATP derivative capable of inducing long-range (>170 Å) structural rearrangements associated with channel activation, establishing a structural basis for key binding site interactions that are the threshold for triggering quaternary structural changes. Our finding that cAMP also induces these structural changes and results in increased channel opening suggests its potential role as an endogenous modulator of RyR1 conductance.
External linksStructure / PubMed:37192614 / PubMed Central
MethodsEM (single particle)
Resolution2.84 - 3.98 Å
Structure data

EMDB-40422, PDB-8sen:
Cryo-EM Structure of RyR1
Method: EM (single particle) / Resolution: 3.49 Å

EMDB-40423, PDB-8seo:
Cryo-EM Structure of RyR1 + ATP-gamma-S
Method: EM (single particle) / Resolution: 3.92 Å

EMDB-40424, PDB-8sep:
Cryo-EM Structure of RyR1 + ADP
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-40425, PDB-8seq:
Cryo-EM Structure of RyR1 + AMP
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-40426, PDB-8ser:
Cryo-EM Structure of RyR1 + Adenosine
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-40427, PDB-8ses:
Cryo-EM Structure of RyR1 + Adenine
Method: EM (single particle) / Resolution: 3.98 Å

EMDB-40428, PDB-8set:
Cryo-EM Structure of RyR1 + cAMP
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-40429, PDB-8seu:
Cryo-EM Structure of RyR1 (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-40430, PDB-8sev:
Cryo-EM Structure of RyR1 + ATP-gamma-S (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 3.17 Å

EMDB-40431, PDB-8sew:
Cryo-EM Structure of RyR1 + ADP (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 2.89 Å

EMDB-40432, PDB-8sex:
Cryo-EM Structure of RyR1 + AMP (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 2.84 Å

EMDB-40433, PDB-8sey:
Cryo-EM Structure of RyR1 + Adenosine (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 2.99 Å

EMDB-40434, PDB-8sez:
Cryo-EM Structure of RyR1 + Adenine (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 3.54 Å

EMDB-40435, PDB-8sf0:
Cryo-EM Structure of RyR1 + cAMP (Local Refinement of TMD)
Method: EM (single particle) / Resolution: 2.9 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM / Adenosine monophosphate

ChemComp-ADN:
ADENOSINE / Adenosine

ChemComp-ADE:
ADENINE / Adenine

ChemComp-CMP:
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / Cyclic adenosine monophosphate

Source
  • oryctolagus cuniculus (rabbit)
  • rabbit (rabbit)
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Calcium ion channel / skeletal muscle / nucleotide / homotetramer

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