Cryo-EM Structure of the Open Human Ether-à-go-go -Related K + Channel hERG

Wang, Weiwei; MacKinnon, Roderick

doi:10.1016/j.cell.2017.03.048

Cited by 432 publications

(866 citation statements)

References 71 publications

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“…The actual VSs are the S4 segments, in the case of the CaV1.1 structure a 3 10 helix [106]. These helices contain positively charged arginine or lysine residues at every third or fourth position [73, 85, 104–107, 110, 121]. Consistent with the crystallography and cryo-EM environment, the S4 segment of the VSs of all reported calcium, sodium, and potassium voltage-gated ion channel structures is in the upstate.…”

Section: Architecture Of the Cav11 And Cav12 Channelmentioning

confidence: 99%

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Calcium channel gating

Hering

Zangerl-Plessl

Beyl

et al. 2018

Pflugers Arch - Eur J Physiol

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Tuned calcium entry through voltage-gated calcium channels is a key requirement for many cellular functions. This is ensured by channel gates which open during membrane depolarizations and seal the pore at rest. The gating process is determined by distinct sub-processes: movement of voltage-sensing domains (charged S4 segments) as well as opening and closure of S6 gates. Neutralization of S4 charges revealed that pore opening of CaV1.2 is triggered by a “gate releasing” movement of all four S4 segments with activation of IS4 (and IIIS4) being a rate-limiting stage. Segment IS4 additionally plays a crucial role in channel inactivation. Remarkably, S4 segments carrying only a single charged residue efficiently participate in gating. However, the complete set of S4 charges is required for stabilization of the open state. Voltage clamp fluorometry, the cryo-EM structure of a mammalian calcium channel, biophysical and pharmacological studies, and mathematical simulations have all contributed to a novel interpretation of the role of voltage sensors in channel opening, closure, and inactivation. We illustrate the role of the different methodologies in gating studies and discuss the key molecular events leading CaV channels to open and to close.Electronic supplementary materialThe online version of this article (10.1007/s00424-018-2163-7) contains supplementary material, which is available to authorized users.

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Section: Architecture Of the Cav11 And Cav12 Channelmentioning

confidence: 99%

“…The impact of this interaction is currently unknown. In comparison, in Kv11.1 [104] and Kv10.1 [105], the voltage-sensing S4 segments are connected to the pore of the same domain by a short linker loop and every S4 has hydrophobic interactions with only the S5 of the same domain.…”

Section: Architecture Of the Cav11 And Cav12 Channelmentioning

confidence: 99%

Calcium channel gating

Hering

Zangerl-Plessl

Beyl

et al. 2018

Pflugers Arch - Eur J Physiol

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“…The recently solved hERG cryo-EM structures at near atomic resolution revealed the existence of hydrophobic pouches protruding from the cavity towards the extracellular side, and a possible role for drug-binding was suggested [22]. However, at least for lubeluzole these regions do not seem to contribute to drug-binding.…”

Section: Discussionmentioning

confidence: 99%

“…methods). The binding site radius was set to 20 Å around the geometric centers of Y652, which lead to a selection including all experimentally observed hERG binding determinants [20, 28, 29], as well as the hydrophobic pouches behind the selectivity filter [22]. 100, 000 operations of the GOLD genetic algorithm were used to dock both enantiomers.…”

Section: Methodsmentioning

confidence: 99%

“…This latter goal was pursued by designing, preparing, and testing two simplified model compounds corresponding to two moieties included in the lubeluzole structure. The obtained experimental results were rationalized by docking simulation on the recently reported cryo-electron microscopy (cryo-EM) structure of hERG [22]. Group efficiency analysis was performed in order to identify the fragment most contributing to binding.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole

Gualdani

Cavalluzzi

Tadini‐Buoninsegni

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking. Methods: We tested the affinity of lubeluzole, its enantiomer, and the racemate for hERG channel using the patch-clamp technique. We synthesized and tested two simplified model compounds corresponding to two moieties included in the lubeluzole structure. The obtained experimental results were rationalized by docking simulation on the recently reported cryo-electron microscopy (cryo-EM) structure of hERG. Group efficiency analysis was performed in order to individuate the fragment most contributing to binding. Results: We found that lubeluzole and its R enantiomer are highly potent inhibitors of human ether-ago-go-related gene (hERG) channel with an IC₅₀ value of 12.9 ± 0.7 nM and 11.3 ± 0.8 nM, respectively. In the presence of lubeluzole, steady-state activation and inactivation of hERG channel were shifted to more negative potentials and inactivation kinetics was accelerated. Mutations of aromatic residues (Y652A and F656A) in the channel inner cavity significantly reduced the inhibitory effect of lubeluzole. Molecular docking simulations performed on the near atomic resolution cryo-electron microscopy structures of hERG supported the role of Y652 and F656 as the main contributors to high affinity binding. Group efficiency analysis indicated that both 1,3-benzothiazol-2-amine and 3-aryloxy-2-propanolamine moieties contribute to drug binding with the former giving higher contribution. Conclusions: This study suggests the possibility to modulate lubeluzole hERG blockade by introducing suitable substituents onto one or both constituting portions of the parent compound in order to either reduce potency (i. e. torsadogenic potential) or potentiate affinity (useful for class III antiarrhythmic and anticancer agent development).

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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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Cryo-EM Structure of the Open Human Ether-à-go-go -Related K + Channel hERG

Cited by 432 publications

References 71 publications

Calcium channel gating

Calcium channel gating

Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole

Ion Channels as Therapeutic Drug Targets

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