7UA1

Structure of PKA phosphorylated human RyR2-R2474S in the closed state in the presence of ARM210

This is a non-PDB format compatible entry.

Summary for 7UA1

• Entry DOI: 10.2210/pdb7ua1/pdb
• EMDB information: 26412
• Descriptor: Ryanodine receptor 2, Peptidyl-prolyl cis-trans isomerase FKBP1B, ZINC ION, ... (5 entities in total)
• Functional Keywords: calcium channel, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 2313694.74

Authors

Miotto, M.C.,Marks, A.R. (deposition date: 2022-03-11, release date: 2022-08-03)

Primary citation

Miotto, M.C.,Weninger, G.,Dridi, H.,Yuan, Q.,Liu, Y.,Wronska, A.,Melville, Z.,Sittenfeld, L.,Reiken, S.,Marks, A.R.
Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment.
Sci Adv, 8:eabo1272-eabo1272, 2022

PubMed Abstract: Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

PubMed: 35857850
DOI: 10.1126/sciadv.abo1272

Experimental method

ELECTRON MICROSCOPY (2.99 Å)