A drug and ATP binding site in type 1 ryanodine receptor.

Abstract

The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is required for excitation-contraction coupling in skeletal and cardiac muscle. Inherited mutations and stress-induced post-translational modifications result in an SR Ca2+ leak that causes skeletal myopathies, heart failure, and exercise-induced sudden death. A class of therapeutics known as Rycals prevent the RyR-mediated leak, are effective in preventing disease progression and restoring function in animal models, and are in clinical trials for patients with muscle and heart disorders. Using cryogenic-electron microscopy, we present a model of RyR1 with a 2.45-Å resolution before local refinement, revealing a binding site in the RY1&2 domain (3.10 Å local resolution), where the Rycal ARM210 binds cooperatively with ATP and stabilizes the closed state of RyR1.

• Authors: Zephan Melville, Haikel Dridi, Qi Yuan, Steven Reiken, Anetta Wronska, Yang Liu, Oliver B Clarke, Andrew R Marks
• Journal: Structure (London, England : 1993) (Structure) Vol. 30 Issue 7 Pg. 1025-1034.e4 (07 07 2022) ISSN: 1878-4186 [Electronic] United States
• PMID: 35580609 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Ryanodine Receptor Calcium Release Channel
• Adenosine Triphosphate
• Calcium

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Binding Sites
• Calcium (metabolism)
• Muscle, Skeletal (metabolism)
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)
• Sarcoplasmic Reticulum (metabolism)