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Structure paper

Title	Structural basis for ryanodine receptor type 2 leak in heart failure and arrhythmogenic disorders.
Journal, issue, pages	Nat Commun, Vol. 15, Issue 1, Page 8080, Year 2024
Publish date	Sep 15, 2024
Authors	Marco C Miotto / Steven Reiken / Anetta Wronska / Qi Yuan / Haikel Dridi / Yang Liu / Gunnar Weninger / Carl Tchagou / Andrew R Marks /
PubMed Abstract	Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of ...Heart failure, the leading cause of mortality and morbidity in the developed world, is characterized by cardiac ryanodine receptor 2 channels that are hyperphosphorylated, oxidized, and depleted of the stabilizing subunit calstabin-2. This results in a diastolic sarcoplasmic reticulum Ca leak that impairs cardiac contractility and triggers arrhythmias. Genetic mutations in ryanodine receptor 2 can also cause Ca leak, leading to arrhythmias and sudden cardiac death. Here, we solved the cryogenic electron microscopy structures of ryanodine receptor 2 variants linked either to heart failure or inherited sudden cardiac death. All are in the primed state, part way between closed and open. Binding of Rycal drugs to ryanodine receptor 2 channels reverts the primed state back towards the closed state, decreasing Ca leak, improving cardiac function, and preventing arrhythmias. We propose a structural-physiological mechanism whereby the ryanodine receptor 2 channel primed state underlies the arrhythmias in heart failure and arrhythmogenic disorders.
External links	Nat Commun / PubMed:39278969 / PubMed Central
Methods	EM (single particle)
Resolution	2.79 - 6.01 Å
Structure data	42458 8uq2 EMDB-42458, PDB-8uq2: Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 2.98 Å 42459 8uq3 EMDB-42459, PDB-8uq3: Structure of human RyR2-S2808D in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.18 Å 42460 8uq4 EMDB-42460, PDB-8uq4: Structure of human RyR2-S2808D in the subprimed state in the presence of H2O2/NOC-12/GSH Method: EM (single particle) / Resolution: 3.64 Å 42461 8uq5 EMDB-42461, PDB-8uq5: Structure of human RyR2-S2808D in the primed state in the presence of Rapamycin Method: EM (single particle) / Resolution: 3.96 Å EMDB-42581: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 2.81 Å EMDB-42582: Constituent EM map: Focused refinement Jsol+CSol of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 2.79 Å EMDB-42583: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 2.79 Å EMDB-42584: Constituent EM map: Focused refinement RY3&4 of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 3.37 Å EMDB-42585: Constituent EM map: Focused refinement RY1&2 of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 3.36 Å EMDB-42586: Constituent EM map: Focused refinement BSol2 of the Structure of human RyR2-S2808D in the subprimed state Method: EM (single particle) / Resolution: 3.57 Å EMDB-42646: Constituent EM map: Focused refinement BSol2 of the Structure of human RyR2-S2808D in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 4.16 Å EMDB-42703: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.53 Å EMDB-42704: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.18 Å EMDB-42705: Constituent EM map: Focused refinement Jsol+CSol of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.1 Å EMDB-42706: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.15 Å EMDB-42707: Constituent EM map: Focused refinement BSol of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.76 Å EMDB-42708: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.95 Å EMDB-42709: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 4.39 Å EMDB-42710: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 5.02 Å EMDB-42722: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.08 Å EMDB-42723: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 2.93 Å EMDB-42724: Constituent EM map: Focused refinement Jsol+CSol of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 2.97 Å EMDB-42725: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 2.91 Å EMDB-42726: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.38 Å EMDB-42727: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.19 Å EMDB-42728: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.29 Å EMDB-42729: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.52 Å EMDB-42730: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.21 Å EMDB-42731: Constituent EM map: Focused refinement Jsol+CSol of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.2 Å EMDB-42732: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.15 Å EMDB-42733: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.79 Å EMDB-42734: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 4.11 Å EMDB-42735: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 5.65 Å EMDB-42736: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.29 Å EMDB-42737: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.15 Å EMDB-42738: Constituent EM map: Focused refinement JSol+CSol of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.03 Å EMDB-42739: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.01 Å EMDB-42740: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.53 Å EMDB-42741: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.82 Å EMDB-42742: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 4.61 Å EMDB-42743: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.12 Å EMDB-42744: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 2.88 Å EMDB-42745: Constituent EM map: Focused refinement JSol+CSol of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 2.94 Å EMDB-42746: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 2.92 Å EMDB-42747: Constituent EM map: Focused refinement CaM of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.47 Å EMDB-42748: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.32 Å EMDB-42749: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.5 Å EMDB-42750: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 5.03 Å EMDB-42751: Raw consensus map of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.56 Å EMDB-42752: Constituent EM map: Focused refinement TaF+TM+CTD of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.3 Å EMDB-42753: Constituent EM map: Focused refinement JSol+CSol of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.1 Å EMDB-42754: Constituent EM map: Focused refinement NTD+SPRY+Calstabin-2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.02 Å EMDB-42755: Constituent EM map: Focused refinement CaM of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.84 Å EMDB-42756: Constituent EM map: Focused refinement RY1&2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.62 Å EMDB-42757: Constituent EM map: Focused refinement RY3&4 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.97 Å EMDB-42758: Constituent EM map: Focused refinement BSol2 of the Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 6.01 Å 42759 8uxc EMDB-42759, PDB-8uxc: Structure of PKA phosphorylated human RyR2-R420Q in the primed state Method: EM (single particle) / Resolution: 2.86 Å 42761 8uxe EMDB-42761, PDB-8uxe: Structure of PKA phosphorylated human RyR2-R420Q in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.53 Å 42762 8uxf EMDB-42762, PDB-8uxf: Structure of PKA phosphorylated human RyR2-R420W in the primed state Method: EM (single particle) / Resolution: 3.13 Å 42763 8uxg EMDB-42763, PDB-8uxg: Structure of PKA phosphorylated human RyR2-R420W in the closed state in the presence of ARM210 Method: EM (single particle) / Resolution: 3.08 Å 42764 8uxh EMDB-42764, PDB-8uxh: Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium Method: EM (single particle) / Resolution: 3.52 Å 42765 8uxi EMDB-42765, PDB-8uxi: Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium Method: EM (single particle) / Resolution: 3.29 Å 42768 8uxl EMDB-42768, PDB-8uxl: Structure of PKA phosphorylated human RyR2-R420W in the primed state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.12 Å 42769 8uxm EMDB-42769, PDB-8uxm: Structure of PKA phosphorylated human RyR2-R420W in the open state in the presence of calcium and calmodulin Method: EM (single particle) / Resolution: 3.56 Å
Chemicals	ChemComp-ZN: Unknown entry ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM ChemComp-KVR: 4-[(7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)methyl]benzoic acid ChemComp-CA*: Unknown entry
Source	homo sapiens (human)
Keywords	MEMBRANE PROTEIN / calcium channel / TRANSPORT PROTEIN

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