Structure of the voltage-gated K
            <sup>+</sup>
            channel Eag1 reveals an alternative voltage sensing mechanism

Whicher, Jonathan R.; MacKinnon, Roderick

doi:10.1126/science.aaf8070

Cited by 277 publications

(537 citation statements)

References 64 publications

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“…The NMR data suggest that the transmembrane extent of S1 in Kv11.1 extends at least from Trp-410 to Leu-432, with a possible break or kink at Thr-425/Pro-426. The NMR data do not support a pre-S1 helical segment in Kv11.1 channels, a feature that is present in the structure of other voltage-gated ion channels (37)(38)(39)(40)(41)(42)(43) but not in the cryo-electron microscopy (cryo-EM) structure of rEAG (50).…”

Section: Structural Extent Of the S1 Helix Of Kv111 Channelsmentioning

confidence: 92%

“…Using a recently published cryo-EM closed-state structure of rat EAG1 (50), in which the S6 activation gate is closed but the voltage sensor domain is in an "activated" conformation (activated-state model), we built a homology model of the Kv11.1 channel that is shown in Fig. 2.…”

Section: Revealing the Extent Of The S1 Helix In Kv111 Channelsmentioning

confidence: 99%

“…Next, we generated a homology model based on the structure of rEAG (50), a related channel protein family member with high sequence similarity to Kv11.1. In the homology model shown in Fig.…”

Section: Structural Extent Of the S1 Helix Of Kv111 Channelsmentioning

confidence: 99%

“…The gray box indicates the extent of the S1 helix based on the cryo-EM structure of rEAG channels (50). B, homology model of a Kv11.1 channel based on the cryo-EM structure of the rEAG channel (50). The S1 helix (shown in white) extends from Pro-405 to Phe-431 (side chains shown in space fill), with no apparent breaks in the helical structure.…”

mentioning

confidence: 99%

“…* denotes fully conserved amino acids, and colon and period denote amino acids with strongly or weakly conserved properties, respectively. The gray box indicates the extent of the S1 helix based on the cryo-EM structure of rEAG channels (50). B, homology model of a Kv11.1 channel based on the cryo-EM structure of the rEAG channel (50).…”

mentioning

confidence: 99%

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The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

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Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in finetuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11

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Section: Structural Extent Of the S1 Helix Of Kv111 Channelsmentioning

confidence: 92%

Section: Revealing the Extent Of The S1 Helix In Kv111 Channelsmentioning

confidence: 99%

Section: Structural Extent Of the S1 Helix Of Kv111 Channelsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

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Ion Channels as Therapeutic Drug Targets

García¹,

Kaczorowski²

2021

Burger's Medicinal Chemistry and Drug Discovery

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Ion channels comprise a large and diverse family of proteins that control many physiological functions. For this reason, a number of inherited diseases result from mutations in specific genes that alter the functions of given ion channels. Drugs used to treat a variety of pathophysiological conditions derive their benefits from interacting with specific ion channel(s), and efforts to develop novel ion channel drugs that would address unmet clinical needs are ongoing in pharmaceutical, biotech, and academic institutions. During the past period of time, major developments in functional screening technologies have afforded the study of these proteins in high‐density formats. In addition, a large body of information concerning the structure of different ion channels has become available. In some cases, intimate details of the interactions between drugs and ion channels have been obtained, which may help with designing more potent and selective ion channel modulators. Although a number of ion channel modulators have entered clinical development, lack of therapeutic efficacy or toxicity issues have caused termination of the development of many of these agents. Nonetheless, with all accumulated experience and new technological advancements, expectations are high for the successful development of novel ion channel modulators in the future.

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The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

et al. 2017

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Voltage‐dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2‐like 1 ( PKD 2L1) forms voltage‐dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Here, we found that the mutation of an asparagine 533 residue (N533Q) in the outer pore loop region of PKD 2L1 caused a marked increase in outward currents induced by depolarization. In addition, the tail current analysis demonstrated that the N533Q mutants are activated during depolarization but the subsequent inactivation does not occur. Interestingly, the N533Q mutants lacked the channel activation triggered by the removal of stimuli such as extracellular alkalization and heating. Our findings suggest that the N533 residue in the outer pore loop region of PKD 2L1 has a key role in the voltage‐dependent channel inactivation.

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Structure of the voltage-gated K ⁺ channel Eag1 reveals an alternative voltage sensing mechanism

Cited by 277 publications

References 64 publications

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Ion Channels as Therapeutic Drug Targets

The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

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Structure of the voltage-gated K + channel Eag1 reveals an alternative voltage sensing mechanism

Cited by 277 publications

References 64 publications

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Ion Channels as Therapeutic Drug Targets

The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

Contact Info

Product

Resources

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Structure of the voltage-gated K ⁺ channel Eag1 reveals an alternative voltage sensing mechanism