Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

Dong, Yanli; Gao, Yongfei; Xu, Shuai; Wang, Yuhang; Yu, Zhuoya; Li, Yue; Li, Bin; Tian, Yuan; Yang, Bei; Zhang, Xuejun C.; Jiang, Dequan; Huang, Zhuo; Zhao, Yan

doi:10.1016/j.celrep.2021.109931

Cited by 49 publications

(78 citation statements)

References 61 publications

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“…All data reported as mean ± SEM. No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported previously in the field 29 , 31 , 60 . Data analyses were performed using Origin 2019b (Origin Lab Corporation), Excel 2016 (Microsoft), GraphPad Prism 6 (GraphPad Software, Inc.), and Adobe illustrator 2018 (Adobe Systems Incorporated).…”

Section: Methodsmentioning

confidence: 87%

“…The Ca V 3.3 structure is further compared with the structure of a high-voltage activated Ca V 2.2 channel 31 (PDB ID: 7VFS), giving rise to an RMSD of ~2.8 Å for 930 Cα-pairs. Some discernible structural differences are observed occurring at the extracellular loops, which would cause incompatibility of Ca V 3.3 with the Ca V 2.2 accessory subunit α2δ, as discussed in the previous report 29 .…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, structures of different subtypes of Ca V channels have been reported in their apo state or in complex with different modulators, providing rich structural insights of the gating and modulation mechanisms of Ca V channels 24 – 31 . In particular, structure of the human Ca V 3.1 channel was resolved.…”

Section: Introductionmentioning

confidence: 99%

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Structure, gating, and pharmacology of human CaV3.3 channel

Geng

et al. 2022

Nat Commun

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The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.

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Section: Methodsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

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Structure, gating, and pharmacology of human CaV3.3 channel

Geng

et al. 2022

Nat Commun

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“…The selectivity filter and the activation gate collapse from four-fold symmetry favorable for sodium coordination to two-fold symmetry that is much narrower in one axis and cannot conduct sodium ( Zhang X. et al, 2012 ; Payandeh et al, 2012 ). The collapsed pore feature is also used in the C-type inactivation of tetrameric K V channels at the selectivity filter ( Hoshi et al, 1991 ), and has been observed in recent cryo-EM structures of the N-type voltage-gated calcium channel Ca V 2.2 ( Dong et al, 2021 ; Gao et al, 2021 ).…”

Section: State-dependent Structure and Function Of Voltage‐gated Sodi...mentioning

confidence: 99%

“…Over the past decades, fenestrations were considered merely as the hydrophobic pathway for neutral drugs to enter the pore from the membrane ( Gamal El-Din et al, 2018b ). However, many recent structures of voltage-gated sodium and calcium channels provide evidence that some drugs have their binding sites that are partially or completely inside the fenestrations ( Figure 6D ) ( Zhao et al, 2019a ; Zhao et al, 2019b ; Jiang et al, 2020 ; Dong et al, 2021 ). Since some residues in the P-loop helices form the roof of the fenestrations, drug binding in the fenestrations may elicit conformational changes of these amino acids and induce a collapse of the selectivity filter to prevent ion permeation.…”

Section: Perspective On Novel Druggable Sites On Voltage‐gated Sodium...mentioning

confidence: 99%

Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Wisedchaisri

El-Din

2022

Front. Pharmacol.

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Voltage-gated ion channels are important drug targets because they play crucial physiological roles in both excitable and non-excitable cells. About 15% of clinical drugs used for treating human diseases target ion channels. However, most of these drugs do not provide sufficient specificity to a single subtype of the channels and their off-target side effects can be serious and sometimes fatal. Recent advancements in imaging techniques have enabled us for the first time to visualize unique and hidden parts of voltage-gated sodium channels in different structural conformations, and to develop drugs that further target a selected functional state in each channel subtype with the potential for high precision and low toxicity. In this review we describe the druggability of voltage-gated sodium channels in distinct functional states, which could potentially be used to selectively target the channels. We review classical drug receptors in the channels that have recently been structurally characterized by cryo-electron microscopy with natural neurotoxins and clinical drugs. We further examine recent drug discoveries for voltage-gated sodium channels and discuss opportunities to use distinct, state-dependent receptor sites in the voltage sensors as unique drug targets. Finally, we explore potential new receptor sites that are currently unknown for sodium channels but may be valuable for future drug discovery. The advancement presented here will help pave the way for drug development that selectively targets voltage-gated sodium channels.

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Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

et al. 2022

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Transient receptor potential vanilloid (TRPV) channels play various important roles in human physiology. As membrane proteins, these channels are modulated by their endogenous lipid environment as the recent wealth of structural studies has revealed functional and structural lipid binding sites. Additionally, it has been shown that exogenous ligands can exchange with some of these lipids to alter channel gating. Here, we used molecular dynamics simulations to examine how one member of the TRPV family, TRPV2, interacts with endogenous lipids and the pharmacological modulator cannabidiol (CBD). By computationally reconstituting TRPV2 into a typical plasma membrane environment, which includes phospholipids, cholesterol, and phosphatidylinositol (PIP) in the inner leaflet, we showed that most of the interacting surface lipids are phospholipids without strong specificity for headgroup types. Intriguingly, we observed that the C-terminal membrane proximal region of the channel binds preferentially to PIP lipids. We also modelled two structural lipids in the simulation: one in the vanilloid pocket and the other in the voltage sensor-like domain (VSLD) pocket. The simulation shows that the VSLD lipid dampens the fluctuation of the VSLD residues, while the vanilloid lipid exhibits heterogeneity both in its binding pose and in its influence on protein dynamics.Addition of CBD to our simulation system led to an open selectivity filter and a structural rearrangement that includes a clockwise rotation of the ankyrin repeat domains, TRP helix, and VSLD. Together, these results reveal the interplay between endogenous lipids and an exogenous ligand and their effect on TRPV2 stability and channel gating.

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Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

Cited by 49 publications

References 61 publications

Structure, gating, and pharmacology of human CaV3.3 channel

Structure, gating, and pharmacology of human CaV3.3 channel

Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Modulation of TRPV2 by endogenous and exogenous ligands: A computational study

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