Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives

The coordinated release of Ca2+ 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-o). To obtain structural insights into the mechanism of RyR1 priming by ATP, we determined several cryo-EM structures of RyR1 bound individually to ATP-gamma-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 A) 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.

Automated summary

The release of Ca2+ from the sarcoplasmic reticulum (SR), facilitated by ryanodine receptors (RyRs), is crucial for excitation-contraction coupling. In this study, cryo-EM structures of RyR1 bound to various ATP derivatives were determined, revealing that AMP is the smallest derivative capable of inducing structural rearrangements associated with channel activation. Additionally, cAMP was found to induce similar structural changes and increase channel opening, suggesting its potential role as an endogenous modulator of RyR1 conductance.