Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives

Cholak, Spencer; Saville, James W.; Zhu, Xing; Berezuk, Alison; Tuttle, K.S.; Haji-Ghassemi, O.; Alvarado, Francisco; Petegem, Filip Van; Subramaniam, Sriram

doi:10.1016/j.str.2023.04.009

Cited by 11 publications

(11 citation statements)

References 55 publications

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“…Notably, this observation aligns with a cryo-EM structure (7M6L), capturing the open state with full-ligand activation . On the contrary, in the closed state, ribose establishes a hydrogen bond with T4979, as evidenced in a cryo-EM structure (8SEO) . Our simulations without Zn 2+ reveal that ATP lacks its interaction at the ribose site (Figure b), resulting in abnormalities in U-motif/S6c interactions and a misalignment of S6c segment (Figure b,c).…”

Section: Resultssupporting

confidence: 80%

“…52 On the contrary, in the closed state, ribose establishes a hydrogen bond with T4979, as evidenced in a cryo-EM structure (8SEO). 55 Our simulations without Zn 2+ reveal that ATP lacks its interaction at the ribose site (Figure 7b), resulting in abnormalities in U-motif/S6c interactions and a misalignment of S6c segment (Figure 6b,c). In contrast, the S6c segment from MD simulations with Zn 2+ maintains an appropriate configuration.…”

Section: Dft-derived Binding Energymentioning

confidence: 90%

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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: Resultssupporting

confidence: 80%

Section: Dft-derived Binding Energymentioning

confidence: 90%

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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“…Close to the transmembrane region are binding sites for Ca 2+ , ATP, and caffeine, which also activate the channel. The binding site for ATP can also be occupied by other adenine derivatives, including cAMP …”

Section: Resultsmentioning

confidence: 99%

“…The binding site for ATP can also be occupied by other adenine derivatives, including cAMP. 19 However, one proposed inhibitory class of molecules, known as rycals, were recently observed bound to the Ry12 domain in complex with an ATP molecule. 18,49 Interestingly, one of our proposed sites for ent-verticilide (L1 in Figure 5) also resides within the Ry12 domain, indicating the potential importance of this domain in regulating the pore opening.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In this headpiece, cryo-EM studies have identified binding sites for native allosteric modulators of the channel function, such as calmodulin (CaM) or FKBP12.0/12.6 . Leveraged synergies between cryo-EM, crystallography, and Förster resonance energy transfer (FRET) have uncovered details of the structural mechanisms modulating the RyR function. ,− Furthermore, recent breakthroughs in cryo-EM technologies have led to near-atomic high-resolution structures of the RyR1 and RyR2. , These include RyR costructures with peptide toxins and small-molecule modulators, both physiologic and pharmacologic, that have been mapped to different regions of the channel complex. ,− …”

Section: Introductionmentioning

confidence: 99%

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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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Propofol binds and inhibits skeletal muscle ryanodine receptor 1

Joseph,

Bu,

Haji-Ghassemi

et al. 2024

British Journal of Anaesthesia

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Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives

Cited by 11 publications

References 55 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

Propofol binds and inhibits skeletal muscle ryanodine receptor 1

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Allosteric modulation of ryanodine receptor RyR1 by nucleotide derivatives

Cited by 11 publications

References 55 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

Propofol binds and inhibits skeletal muscle ryanodine receptor 1

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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