8SF0

Cryo-EM Structure of RyR1 + cAMP (Local Refinement of TMD)

Summary for 8SF0

• Entry DOI: 10.2210/pdb8sf0/pdb
• EMDB information: 40422 40423 40424 40425 40426 40427 40428 40429 40430 40431 40432 40433 40434 40435
• Descriptor: Ryanodine receptor 1, ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE, ZINC ION (3 entities in total)
• Functional Keywords: calcium ion channel, skeletal muscle, nucleotide, homotetramer, transport protein
• Biological source: Oryctolagus cuniculus (rabbit)
• Total number of polymer chains: 4
• Total formula weight: 2265212.96

Authors

Cholak, S.,Saville, J.W.,Zhu, X.,Berezuk, A.M.,Tuttle, K.S.,Haji-Ghassemi, O.,Van Petegem, F.,Subramaniam, S. (deposition date: 2023-04-10, release date: 2023-05-24, Last modification date: 2024-10-23)

Primary citation

Cholak, S.,Saville, J.W.,Zhu, X.,Berezuk, A.M.,Tuttle, K.S.,Haji-Ghassemi, O.,Alvarado, F.J.,Van Petegem, F.,Subramaniam, S.
Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives.
Structure, 31:790-800.e4, 2023

PubMed Abstract: 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.

PubMed: 37192614
DOI: 10.1016/j.str.2023.04.009

Experimental method

ELECTRON MICROSCOPY (2.9 Å)