Down-State Model of the KvAP Full Channel

Schow, Eric V.; Nizkorodov, Alexandr; Freites, J. Alfredo; White, Stephen H.; Tobias, Douglas J.

doi:10.1016/j.bpj.2009.12.1709

Cited by 3 publications

(2 citation statements)

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“…Disulfide bond formation between R1C and I241C in S1 or I287C in S2 in the closed state (Campos et al, 2007) also supports close proximity of R1 and E283 in the resting state. Several structural models of Shaker , Kv1.2 and KvAP channels in the resting state have been developed using these experimental data to constrain the position of R1 close to E283 (Yarov-Yarovoy et al, 2006; Campos et al, 2007; Pathak et al, 2007; Nishizawa and Nishizawa, 2008; Schow et al, 2010; Vargas et al, 2011). Using molecular dynamics simulations to calculate the gating charge transferred when the Kv1.2 S4 segment moves from a resting position, where R1 and E283 interact, to an activated conformation, where R4 and E283 interact, resulted in a value of ∼12–12.7 e 0 (Khalili-Araghi et al, 2010), which is in good agreement with experimental findings (Bezanilla, 2000).…”

Section: Regulation Of Voltage Sensor Movement In Herg and Shaker Chamentioning

confidence: 99%

Voltage-Dependent Gating of hERG Potassium Channels

Cheng¹,

Claydon²

2012

Front. Pharmacol.

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The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv) channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4–S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-à-go-go related gene, hERG), which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure–function relationships underlying activation and deactivation gating in Shaker and hERG channels, with a focus on the roles of the voltage-sensing domain and the S4–S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter-charge interactions. More recent data suggest that key amino acid differences in the hERG voltage-sensing unit and S4–S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor.

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Section: Regulation Of Voltage Sensor Movement In Herg and Shaker Chamentioning

confidence: 99%

Voltage-Dependent Gating of hERG Potassium Channels

Cheng¹,

Claydon²

2012

Front. Pharmacol.

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“…Yet, this structure provides us with a good idea of what a closed Kv channel looks like, mostly in the pore region. Hence, models of the resting states of other channels (Hv1, NaChBac, and the plant KAT channel) have been derived from homology modeling methods, using among others, the MlotiK structure as templates (Shafrir et al, 2008; Schow et al, 2010; DeCaen et al, 2011; Wood et al, 2012). All these models bear similarities, as they place S4 inwards.…”

Section: Molecular Insight Into the Function Of Kv Channelsmentioning

confidence: 99%

Molecular Dynamics Simulations of Voltage-Gated Cation Channels: Insights on Voltage-Sensor Domain Function and Modulation

Delemotte¹,

Klein²,

Tarek³

2012

Front. Pharmacol.

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Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (VGCC) has been largely understood thanks to results stemming from electrophysiology, pharmacology, spectroscopy, and structural biology. Over the past decade, computational methods such as molecular dynamics (MD) simulations have also contributed, providing molecular level information that can be tested against experimental results, thereby allowing the validation of the models and protocols. Importantly, MD can shed light on elements of VGCC function that cannot be easily accessed through “classical” experiments. Here, we review the results of recent MD simulations addressing key questions that pertain to the function and modulation of the VGCC’s voltage-sensor domain (VSD) highlighting: (1) the movement of the S4-helix basic residues during channel activation, articulating how the electrical driving force acts upon them; (2) the nature of the VSD intermediate states on transitioning between open and closed states of the VGCC; and (3) the molecular level effects on the VSD arising from mutations of specific S4 positively charged residues involved in certain genetic diseases.

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Studying Kv Channels Function using Computational Methods

Deyawe

Kasimova

Delemotte

et al. 2017

Methods in Molecular Biology

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In recent years, molecular modeling techniques, combined with MD simulations, provided significant insights on voltage-gated (Kv) potassium channels intrinsic properties. Among the success stories are the highlight of molecular level details of the effects of mutations, the unraveling of several metastable intermediate states, and the influence of a particular lipid, PIP, in the stability and the modulation of Kv channel function. These computational studies offered a detailed view that could not have been reached through experimental studies alone. With the increase of cross disciplinary studies, numerous experiments provided validation of these computational results, which endows an increase in the reliability of molecular modeling for the study of Kv channels. This chapter offers a description of the main techniques used to model Kv channels at the atomistic level.

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Down-State Model of the KvAP Full Channel

Cited by 3 publications

References 0 publications

Voltage-Dependent Gating of hERG Potassium Channels

Voltage-Dependent Gating of hERG Potassium Channels

Molecular Dynamics Simulations of Voltage-Gated Cation Channels: Insights on Voltage-Sensor Domain Function and Modulation

Studying Kv Channels Function using Computational Methods

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