Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.
12 affiliations
- 1Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
- 2Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
- 3Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA.
- 4The National Resource of Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
- 5Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev, Beer Sheva, Israel.
- 6Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, USA.
- 7Pain Research Center, New York University, New York, NY, USA.
- 8Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
- 9Department of Biological Sciences, Columbia University, New York, NY, USA.
- 10Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
- 11Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
- 12Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA. [email protected].
Abstract
Malignant hyperthermia (MH) is a pharmacogenetic condition triggered by volatile anesthetics, which activate MH susceptible mutants of ryanodine receptor 1 (RyR1). The precise binding sites and mechanisms of the therapeutic dantrolene and MH triggers have remained unclear. Here, we present structures of RyR1 bound to dantrolene and the MH trigger 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change. Functional analyses confirm ATP or ADP is required for dantrolene inhibition, and a single point mutation disrupting this peripheral ATP site abolishes this ATP/ADP-dependent inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules even in the presence of excess ATP, indicating a role in ATP/ADP ratio sensing. Additionally, we identified four 4CmC binding sites, revealing one primary binding site in an amphipathic cavity in the core solenoid, and three auxiliary binding sites in the EF-hand, transmembrane, and RY12 domains. These findings offer insights into the binding modes and mechanisms of MH-linked molecules, and reveal the RY12 domain's regulatory role as a promiscuous sensor for adenine nucleotides and small ligands.
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BibTeX
@article{kim2026structural,
title = {{Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.}},
author = {Kookjoo Kim and Huan Li and Qi Yuan and Zephan Melville and Ran Zalk and Amédée des Georges and Joachim Frank and Wayne A Hendrickson and Andrew R Marks and Oliver B Clarke},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-76519-y},
url = {https://europepmc.org/article/MED/42838934},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.
AU - Kookjoo Kim
AU - Huan Li
AU - Qi Yuan
AU - Zephan Melville
AU - Ran Zalk
AU - Amédée des Georges
AU - Joachim Frank
AU - Wayne A Hendrickson
AU - Andrew R Marks
AU - Oliver B Clarke
PY - 2026
DA - 2026/09/04
JO - Nature communications
DO - 10.1038/s41467-026-76519-y
UR - https://europepmc.org/article/MED/42838934
AB - Malignant hyperthermia (MH) is a pharmacogenetic condition triggered by volatile anesthetics, which activate MH susceptible mutants of ryanodine receptor 1 (RyR1). The precise binding sites and mechanisms of the therapeutic dantrolene and MH triggers have remained unclear. Here, we present structures of RyR1 bound to dantrolene and the MH trigger 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change. Functional analyses confirm ATP or ADP is required for dantrolene inhibition, and a single point mutation disrupting this peripheral ATP site abolishes this ATP/ADP-dependent inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules even in the presence of excess ATP, indicating a role in ATP/ADP ratio sensing. Additionally, we identified four 4CmC binding sites, revealing one primary binding site in an amphipathic cavity in the core solenoid, and three auxiliary binding sites in the EF-hand, transmembrane, and RY12 domains. These findings offer insights into the binding modes and mechanisms of MH-linked molecules, and reveal the RY12 domain's regulatory role as a promiscuous sensor for adenine nucleotides and small ligands.
SN - 2041-1723
ER -