Cryo-EM Structure of K+-Bound hERG Channel Complexed with the Blocker Astemizole

Asai, Tatsuki; Adachi, Naruhiko; Moriya, Toshio; Oki, Hideyuki; Maru, Takamitsu; Kawasaki, Masato; Suzuki, Kenzi; Chen, Sisi; Ishii, Ryohei; Yonemori, Kazuko; Igaki, S.; Yasuda, Satoshi; Ogasawara, Satoshi; Senda, Toshiya; Murata, Takeshi

doi:10.1016/j.str.2020.12.007

Cited by 63 publications

(60 citation statements)

References 47 publications

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“…Many potassium channels are blocked by compounds that act within the central cavity 124 – 126 , 146 and functional studies have long indicated that K 2P s share this proclivity for block from the intracellular side 74 , 142 , 147 ( Table 1 ). Structural definition of the Vestibule site delimited by the X-gate in K 2P 3.1 (TASK-1) 38 together with prior studies identifying the TASK subfamily central cavity as a hotspot for the action of a varied antagonists 111 highlight the potential for modulators to act in the K 2P inner cavity.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Natale

Deal

Minor

2021

Journal of Molecular Biology

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Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K 2P ( KCNK ) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K 2P s contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K 2P s have established the basic architecture of this channel family, revealed key moving parts involved in K 2P function, uncovered the importance of asymmetric pinching and dilation motions in the K 2P selectivity filter (SF) C-type gate, and defined two K 2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K 2P :modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K 2P activity. Such knowledge should catalyze development of new K 2P modulators to probe function and treat a wide range of disorders.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Natale

Deal

Minor

2021

Journal of Molecular Biology

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“…The authors suggest that the structure may be in a possible inactivated state when compared to a non-inactivating S631A mutant with F627 shifted slightly into the conduction path. However, a more recent cryo-EM structure of a proposed inactivated state of hERG also shows F627 pointed away from the conduction path, but with a nearly 2 Å increase between carbonyl oxygens in the S1 position; inactivation in this case being the loss of K + ion coordination, not necessarily the orientation of F627 (Asai et al, 2021). In comparison, our m1 and m2 cryo-EM-refined starting models have S1 diameters of 7.2 Å; more open than their archetype hERG structure, but clearly more constricted than the newly proposed inactivated structure.…”

Section: Discussionmentioning

confidence: 96%

Structural modeling of the hERG potassium channel and associated drug interactions

Malý

Emigh²,

DeMarco³

et al. 2021

Preprint

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The voltage-gated potassium channel, KV11.1, encoded by the human Ether-à-go-go-Related Gene (hERG) is expressed in cardiac myocytes, where it is crucial for the membrane repolarization of the action potential. Gating of hERG channel is characterized by rapid, voltage-dependent, C-type inactivation, which blocks ion conduction and is suggested to involve constriction of the selectivity filter. Mutations S620T and S641A/T within the selectivity filter region of hERG have been shown to alter the voltage-dependence of channel inactivation. Because hERG channel blockade is implicated in a number of drug-induced arrhythmias associated with both the open and inactivated states, we simulated the effects of these mutations to elucidate conformational changes associated with hERG channel inactivation and differences in drug binding between the two states. Rosetta modeling of the S641A fast-inactivating mutation revealed a lateral shift of F627 side chain in the selectivity filter into the central channel axis along the ion conduction pathway and formation of a fenestration region below the selectivity filter. Rosetta modeling of the non-inactivating mutations S620T and S641T suggested a potential molecular mechanism preventing F627 side chain from shifting into the ion conduction pathway during the proposed inactivation process. Furthermore, we used Rosetta docking to explore the binding mechanism of highly selective and potent hERG blockers - dofetilide, terfenadine, and E4031. Our results correlate well with existing experimental evidence involving interactions of these drugs with key hERG residues Y652 and F656 inside the pore and reveal potential ligand binding interactions within fenestration region in an inactivated state.

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“…4) The first cryo-EM hERG structures solved by Wang et al [28], in which the authors proposed that blockers occupy some or all of the "hydrophobic pockets" residing inferior to the selectivity filter. 5) A recent cryo-EM structure of astemizole-bound hERG solved by Asai et al [7] (7CN1). 6) Recent cryo-EM structures of flecainide and quinidine-bound Nav1.5, in which both blockers are fully buried within the pore (as claimed for astemizole-bound hERG and may be assumed for other hERG blockers as well).…”

Section: Discussion Herg Blockers Undergo Atypical Bindingmentioning

confidence: 99%

“…Astemizole was docked in the astemizole-bound structure (PDB code = 7CN1 [7]) using the Glide tool in Maestro (noting that astemizole was omitted from this structure for unexplained reasons).…”

Section: ) Bright Blue = 100% H Visitsmentioning

confidence: 99%

General structure-free energy relationships of hERG blocker binding under native cellular conditions

Wan¹,

Spiru²,

Williams³

et al. 2021

Preprint

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We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water ('the solvation field') relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We analyzed blockade of the ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as 'BP') into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as 'BC') occupying the cytoplasmic 'antechamber' of hERG; and 2) undergo second-order entry to the antechamber, followed by first-order association of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polar pore is solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereas blocker BP moieties are solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, the blocker solvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with blocker potency and Redfern safety classification.

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Cryo-EM Structure of K+-Bound hERG Channel Complexed with the Blocker Astemizole

Cited by 63 publications

References 47 publications

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels

Structural modeling of the hERG potassium channel and associated drug interactions

General structure-free energy relationships of hERG blocker binding under native cellular conditions

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