Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases

Iyer, Kavita A.; Barnakov, Vadim; Samsó, Montserrat

doi:10.1016/j.coph.2022.102327

Cited by 8 publications

(7 citation statements)

References 77 publications

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“…Another crucial residue pair contact within the CD/S2−S3 loop involves the formation of a salt bridge between E3757 and K4723 (Figure b), positioned in close proximity to F3753. The mutation K4723Q has been linked to central core disease (CCD), as it disrupts the E3757/K4723 interaction, leading to abnormal CD/S2−S3 loop connections. , The effect of this disruption has been shown by MD simulations in the absence of Zn 2+ , where a weakened interaction between E3757 and K4723 is observed, which we attribute to the highly fluctuating location of F3753 (Figure S8a). Consequently, the presence of Zn 2+ in the CTD-binding pocket of RyR1 plays a crucial role in maintaining the proper orientation of the CTD.…”

Section: Resultsmentioning

confidence: 78%

Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

Taweechat,

Boonamnaj,

Samsó

et al. 2024

J. Phys. Chem. B

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Ryanodine receptor type 1 (RyR1) is a Ca 2+ -release channel central to skeletal muscle excitation−contraction (EC) coupling. RyR1's cryo-EM structures reveal a zinc-finger motif positioned within the cytoplasmic C-terminal domain (CTD). Yet, owing to limitations in cryo-EM resolution, RyR1 structures lack precision in detailing the metal coordination structure, prompting the need for an accurate model. In this study, we employed molecular dynamics (MD) simulations and the density functional theory (DFT) method to refine the binding characteristics of Zn 2+ in the zinc-finger site of the RyR1 channel. Our findings also highlight substantial conformational changes in simulations conducted in the absence of Zn 2+ . Notably, we observed a loss of contact at the interface between protein domains proximal to the zinc-finger site, indicating a crucial role of Zn 2+ in maintaining structural integrity and interdomain interactions within RyR1. Furthermore, this study provides valuable insights into the modulation of ATP, Ca 2+ , and caffeine binding, shedding light on the intricate relationship between Zn 2+ coordination and the dynamic behavior of RyR1. Our integrative approach combining MD simulations and DFT calculations enhances our understanding of the molecular mechanisms governing ligand binding in RyR1.

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Section: Resultsmentioning

confidence: 78%

Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

Taweechat,

Boonamnaj,

Samsó

et al. 2024

J. Phys. Chem. B

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“…In the L2 location, ent -verticilide may affect protomer–protomer interactions within the RyR2 channel complex. Although both L1 and L2 are quite far from the channel pore, modulation of the RyR opening is known to involve long-range structural pathways of long-distance allostery. , …”

Section: Resultsmentioning

confidence: 99%

“…Although both L1 and L2 are quite far from the channel pore, modulation of the RyR opening is known to involve long-range structural pathways of long-distance allostery. 47,48 Based on the FRET range of our donor−acceptor pair, we can detect acceptor-labeled ligands bound throughout the entire cytoplasmic domain. Because the RyR TM domain is outside this range, we cannot completely rule out binding locations in or near the pore.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Šeflová,

Schwarz,

Smith

et al. 2023

ACS Chem. Biol.

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Hyperactivity of cardiac sarcoplasmic reticulum (SR) ryanodine receptor (RyR2) Ca 2+ -release channels contributes to heart failure and arrhythmias. Reducing the RyR2 activity, particularly during cardiac relaxation (diastole), is a desirable therapeutic goal. We previously reported that the unnatural enantiomer (ent) of an insect-RyR activator, verticilide, inhibits porcine and mouse RyR2 at diastolic (nanomolar) Ca 2+ and has in vivo efficacy against atrial and ventricular arrhythmia. To determine the ent-verticilide structural mode of action on RyR2 and guide its further development via medicinal chemistry structure−activity relationship studies, here, we used fluorescence lifetime (FLT)measurements of Forster resonance energy transfer (FRET) in HEK293 cells expressing human RyR2. For these studies, we used an RyR-specific FRET molecular-toolkit and computational methods for trilateration (i.e., using distances to locate a point of interest). Multiexponential analysis of FLT-FRET measurements between four donor-labeled FKBP12.6 variants and acceptorlabeled ent-verticilide yielded distance relationships placing the acceptor probe at two candidate loci within the RyR2 cryo-EM map. One locus is within the Ry12 domain (at the corner periphery of the RyR2 tetrameric complex). The other locus is sandwiched at the interface between helical domain 1 and the SPRY3 domain. These findings document RyR2-target engagement by ent-verticilide, reveal new insight into the mechanism of action of this new class of RyR2-targeting drug candidate, and can serve as input in future computational determinations of the ent-verticilide binding site on RyR2 that will inform structure−activity studies for lead optimization.

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“…The mechanism is thought to be the mutation of RYR1 gene in the 19th chromosome (19q13.1), resulting in chronic leakage of calcium channels and mitochondrial damage leading to limpness and weakness [ 12 ]. It is reported that hundreds of mutations of RYR1 gene have been related with the central core disease [ 13 ]. The patients with central core disease may have facial dysmorphism (retrognathism, high-arched palate) causing difficult airway management or spinal abnormalities and chest deformity producing small lung volumes [ 14 ], which are the risk factors of respiratory is informative and practical failure postoperatively.…”

Section: Discussionmentioning

confidence: 99%

Perioperative management of bronchoscopy in a child patient with central core disease: A case report and literature review

Li,

Ji,

Nie

et al. 2024

International Journal of Surgery Case Reports

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Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases

Cited by 8 publications

References 77 publications

Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Perioperative management of bronchoscopy in a child patient with central core disease: A case report and literature review

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Three-dimensional perspective on ryanodine receptor mutations causing skeletal and cardiac muscle-related diseases

Cited by 8 publications

References 77 publications

Significance of Zn2+ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

Significance of Zn2+ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

RyR2 Binding of an Antiarrhythmic Cyclic Depsipeptide Mapped Using Confocal Fluorescence Lifetime Detection of FRET

Perioperative management of bronchoscopy in a child patient with central core disease: A case report and literature review

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Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics

Significance of Zn²⁺ in RyR1 for Structural Integrity and Ligand Binding: Insight from Molecular Dynamics