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- PDB-8xlh: Structure of chimeric RyR-I4657M/G4819E -

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Basic information

Entry
Database: PDB / ID: 8xlh
TitleStructure of chimeric RyR-I4657M/G4819E
Components
  • Calmodulin-1
  • Peptidyl-prolyl cis-trans isomerase FKBP1B
  • Ryanodine receptor 1
KeywordsMEMBRANE PROTEIN / Ryanodine receptor / Ion channel
Function / homology
Function and homology information


ATP-gated ion channel activity / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / terminal cisterna / insulin secretion involved in cellular response to glucose stimulus / ryanodine receptor complex ...ATP-gated ion channel activity / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / negative regulation of calcium-mediated signaling / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / neuronal action potential propagation / terminal cisterna / insulin secretion involved in cellular response to glucose stimulus / ryanodine receptor complex / ryanodine-sensitive calcium-release channel activity / CaM pathway / Cam-PDE 1 activation / Sodium/Calcium exchangers / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Calmodulin induced events / response to redox state / Reduction of cytosolic Ca++ levels / Activation of Ca-permeable Kainate Receptor / ossification involved in bone maturation / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Loss of phosphorylation of MECP2 at T308 / 'de novo' protein folding / CREB1 phosphorylation through the activation of Adenylate Cyclase / negative regulation of heart rate / CaMK IV-mediated phosphorylation of CREB / PKA activation / negative regulation of high voltage-gated calcium channel activity / Glycogen breakdown (glycogenolysis) / positive regulation of ryanodine-sensitive calcium-release channel activity / CLEC7A (Dectin-1) induces NFAT activation / Activation of RAC1 downstream of NMDARs / negative regulation of calcium ion export across plasma membrane / organelle localization by membrane tethering / skin development / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / FK506 binding / presynaptic endocytosis / positive regulation of axon regeneration / regulation of cardiac muscle cell action potential / negative regulation of ryanodine-sensitive calcium-release channel activity / organelle membrane / Synthesis of IP3 and IP4 in the cytosol / regulation of cell communication by electrical coupling involved in cardiac conduction / Phase 0 - rapid depolarisation / Negative regulation of NMDA receptor-mediated neuronal transmission / Unblocking of NMDA receptors, glutamate binding and activation / cellular response to caffeine / RHO GTPases activate PAKs / calcineurin-mediated signaling / intracellularly gated calcium channel activity / outflow tract morphogenesis / Ion transport by P-type ATPases / Uptake and function of anthrax toxins / regulation of ryanodine-sensitive calcium-release channel activity / Long-term potentiation / Calcineurin activates NFAT / Regulation of MECP2 expression and activity / protein phosphatase activator activity / smooth muscle contraction / DARPP-32 events / response to vitamin E / Smooth Muscle Contraction / catalytic complex / toxic substance binding / detection of calcium ion / regulation of cardiac muscle contraction / RHO GTPases activate IQGAPs / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / smooth endoplasmic reticulum / striated muscle contraction / presynaptic cytosol / voltage-gated calcium channel activity / calcium channel inhibitor activity / cellular response to interferon-beta / Protein methylation / T cell proliferation / Activation of AMPK downstream of NMDARs / skeletal muscle fiber development / Ion homeostasis / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / eNOS activation / regulation of calcium-mediated signaling / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / titin binding / muscle contraction / voltage-gated potassium channel complex / sarcoplasmic reticulum membrane / release of sequestered calcium ion into cytosol / sperm midpiece / substantia nigra development / calcium channel complex / calcium channel regulator activity / calyx of Held / FCERI mediated Ca+2 mobilization / Ras activation upon Ca2+ influx through NMDA receptor / protein maturation / FCGR3A-mediated IL10 synthesis / cellular response to calcium ion
Similarity search - Function
Ryanodine receptor, SPRY domain 2 / : / Ryanodine receptor junctional solenoid repeat / Ryanodine Receptor TM 4-6 / Ryanodine receptor / Ryanodine receptor, SPRY domain 1 / Ryanodine receptor, SPRY domain 3 / Ryanodine Receptor TM 4-6 / Ryanodine receptor Ryr / RyR domain ...Ryanodine receptor, SPRY domain 2 / : / Ryanodine receptor junctional solenoid repeat / Ryanodine Receptor TM 4-6 / Ryanodine receptor / Ryanodine receptor, SPRY domain 1 / Ryanodine receptor, SPRY domain 3 / Ryanodine Receptor TM 4-6 / Ryanodine receptor Ryr / RyR domain / : / RyR/IP3 receptor binding core, RIH domain superfamily / RyR/IP3R Homology associated domain / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / RyR and IP3R Homology associated / Inositol 1,4,5-trisphosphate/ryanodine receptor / RIH domain / : / MIR motif / MIR domain / MIR domain profile. / Domain in ryanodine and inositol trisphosphate receptors and protein O-mannosyltransferases / Mir domain superfamily / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / : / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / EF-hand domain pair / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / CAFFEINE / Calmodulin-1 / Ryanodine receptor 1 / Peptidyl-prolyl cis-trans isomerase FKBP1B
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsLin, L. / Wang, C. / Wang, W. / Jiang, H. / Yuchi, Z.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32372580 China
National Natural Science Foundation of China (NSFC)32022073 China
Ministry of Science and Technology (MoST, China)2022YFE0108400 China
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structures of ryanodine receptors and diamide insecticides reveal the mechanisms of selectivity and resistance.
Authors: Lianyun Lin / Changshi Wang / Wenlan Wang / Heng Jiang / Takashi Murayama / Takuya Kobayashi / Hadiatullah Hadiatullah / Yu Seby Chen / Shunfan Wu / Yiwen Wang / Henryk Korza / Yucheng Gu / ...Authors: Lianyun Lin / Changshi Wang / Wenlan Wang / Heng Jiang / Takashi Murayama / Takuya Kobayashi / Hadiatullah Hadiatullah / Yu Seby Chen / Shunfan Wu / Yiwen Wang / Henryk Korza / Yucheng Gu / Yan Zhang / Jiamu Du / Filip Van Petegem / Zhiguang Yuchi /
Abstract: The resistance of pests to common insecticides is a global issue that threatens food production worldwide. Diamide insecticides target insect ryanodine receptors (RyRs), causing uncontrolled calcium ...The resistance of pests to common insecticides is a global issue that threatens food production worldwide. Diamide insecticides target insect ryanodine receptors (RyRs), causing uncontrolled calcium release from the sarcoplasmic and endoplasmic reticulum. Despite their high potency and species selectivity, several resistance mutations have emerged. Using a chimeric RyR (chiRyR) approach and cryo-electron microscopy (cryo-EM), we investigate how insect RyRs engage two different diamide insecticides from separate families: flubendiamide, a phthalic acid derivative, and tetraniliprole, an anthranilic compound. Both compounds target the same site in the transmembrane region of the RyR, albeit with different poses, and promote channel opening through coupling with the pore-forming domain. To explore the resistance mechanisms, we also solve two cryo-EM structures of chiRyR carrying the two most common resistance mutations, I4790M and G4946E, both alone and in complex with the diamide insecticide chlorantraniliprole. The resistance mutations perturb the local structure, directly reducing the binding affinity and altering the binding pose. Our findings elucidate the mode of action of different diamide insecticides, reveal the molecular mechanism of resistance mutations, and provide important clues for the development of novel pesticides that can bypass the resistance mutations.
History
DepositionDec 26, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ryanodine receptor 1
E: Peptidyl-prolyl cis-trans isomerase FKBP1B
I: Calmodulin-1
D: Ryanodine receptor 1
H: Peptidyl-prolyl cis-trans isomerase FKBP1B
L: Calmodulin-1
C: Ryanodine receptor 1
G: Peptidyl-prolyl cis-trans isomerase FKBP1B
K: Calmodulin-1
B: Ryanodine receptor 1
F: Peptidyl-prolyl cis-trans isomerase FKBP1B
J: Calmodulin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)2,380,26128
Polymers2,377,03312
Non-polymers3,22716
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 12 molecules ADCBEHGFILKJ

#1: Protein
Ryanodine receptor 1 / RYR-1 / RyR1 / Skeletal muscle calcium release channel / Skeletal muscle ryanodine receptor / ...RYR-1 / RyR1 / Skeletal muscle calcium release channel / Skeletal muscle ryanodine receptor / Skeletal muscle-type ryanodine receptor / Type 1 ryanodine receptor


Mass: 565970.562 Da / Num. of mol.: 4 / Mutation: R4563K, F4564Y,C4657M, L4792S,G4819E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: RYR1 / Production host: Homo sapiens (human) / References: UniProt: P11716
#2: Protein
Peptidyl-prolyl cis-trans isomerase FKBP1B / PPIase FKBP1B / 12.6 kDa FK506-binding protein / FKBP-12.6 / FK506-binding protein 1B / FKBP-1B / ...PPIase FKBP1B / 12.6 kDa FK506-binding protein / FKBP-12.6 / FK506-binding protein 1B / FKBP-1B / Immunophilin FKBP12.6 / Rotamase / h-FKBP-12


Mass: 11667.305 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1B, FKBP12.6, FKBP1L, FKBP9, OTK4 / Production host: Escherichia coli (E. coli) / References: UniProt: P68106, peptidylprolyl isomerase
#3: Protein
Calmodulin-1


Mass: 16620.402 Da / Num. of mol.: 4 / Mutation: E32A, E68A, E105A, E141A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CALM1, CALM, CAM, CAM1 / Production host: Escherichia coli (E. coli) / References: UniProt: P0DP23

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Non-polymers , 4 types, 16 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#6: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#7: Chemical
ChemComp-CFF / CAFFEINE / 3,7-DIHYDRO-1,3,7-TRIMETHYL-1H-PURINE-2,6-DIONE


Mass: 194.191 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H10N4O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Chimeric RyR-C4657M/G4819E Ca2+/ATP/caffeine/CaM1234 / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightValue: 2.54 MDa / Experimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 28189 / Symmetry type: POINT

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