Individual Ion Binding Sites in the K+ Channel Play Distinct Roles in C-type Inactivation and in Recovery from Inactivation

Matulef, Kimberly; Annen, Alvin W.; Nix, Jay C.; Valiyaveetil, Francis I.

doi:10.1016/j.str.2016.02.021

Cited by 41 publications

(59 citation statements)

References 61 publications

(97 reference statements)

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“…These experimental observations inspired a provocative idea in which the occupancy of the second K + -binding site is required for channel inactivation. This hypothesis was just elegantly demonstrated (48) and provides an explanation to the permeant-ion dependence of hysteresis and C-type inactivation in KcsA. Rb + and Cs + have a stronger interaction with the channel SF than K + , reducing significantly the single-channel conductance (46,49).…”

Section: Discussionmentioning

confidence: 85%

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

Tilegenova

Cortés

Cuello

2017

Proc. Natl. Acad. Sci. U.S.A.

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Mode-shift or hysteresis has been reported in ion channels. Voltageshift for gating currents is well documented for voltage-gated cation channels (VGCC), and it is considered a voltage-sensing domain's (VSD) intrinsic property. However, uncoupling the Shaker K + channel's pore domain (PD) from the VSD prevented the modeshift of the gating currents. Consequently, it was proposed that an open-state stabilization of the PD imposes a mechanical load on the VSD, which causes its mode-shift. Furthermore, the mode-shift displayed by hyperpolarization-gated cation channels is likely caused by structural changes at the channel's PD similar to those underlying C-type inactivation. To demonstrate that the PD of VGCC undergoes hysteresis, it is imperative to study its gating process in the absence of the VSD. A back-door strategy is to use KcsA (a K + channel from the bacteria Streptomyces lividans) as a surrogate because it lacks a VSD and exhibits an activation coupled to C-type inactivation. By directly measuring KcsA's activation gate opening and closing in conditions that promote or halt C-type inactivation, we have found (i) that KcsA undergoes mode-shift of gating when having K + as the permeant ion; (ii) that Cs + or Rb + , known to halt C-inactivation, prevented mode-shift of gating; and (iii) that, in the total absence of C-type inactivation, KcsA's mode-shift was prevented. Finally, our results demonstrate that an allosteric communication causes KcsA's activation gate to "remember" the conformation of the selectivity filter, and hence KcsA requires a different amount of energy for opening than for closing.hysteresis | KcsA | potassium channels | mode-shift | C-type inactivation

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Section: Discussionmentioning

confidence: 85%

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

Tilegenova

Cortés

Cuello

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Similar changes were observed in a mutant constitutively active at neutral pH, which were suggested to be a structural basis for C-type inactivation 36 . Subsequent studies showed that a maneuver that prevents the rotation of the Val76-Gly77 bond does not prevent inactivation, and that K + occupancy at IS2-IS4, but not at IS1, affects inactivation kinetics 37, 38 . The difference between our present structural findings in a Kv channel and those pertaining to inactivation in KcsA reflects the likely case that multiple types of structural changes in the selectivity filter can give rise to non-conduction.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of an inactivated mutant mammalian voltage-gated K+ channel

Pau

Zhou

Ramu

et al. 2017

Nat Struct Mol Biol

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C-type inactivation underlies important roles played by voltage-gated K+ (Kv) channels. Functional studies have provided strong evidence that a common underlying cause of this type of inactivation is an alteration near the extracellular end of the channel's ion selectivity filter. Unlike N-type inactivation, which is known to reflect occlusion of the channel's intracellular end, the structural mechanism of C-type inactivation remains controversial and may have many detailed variations. Here, we report that in voltage-gated Shaker K+ channels lacking N-type inactivation, a mutation enhancing inactivation disrupts the outermost K+ site in the selectivity filter. Furthermore, in a crystal structure of the Kv1.2-2.1 chimeric channel bearing the same mutation, the outermost K+ site, which is formed by eight carbonyl oxygen atoms, appears to be slightly too small to readily accommodate a K+ ion and in fact exhibits little ion density; this structural finding is consistent with the functional hallmark characteristic of C-type inactivation.

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“…Although the complete experimental structure of the hERG channel is yet to be resolved, the three‐dimensional structures of parts of the hERG domains, such as cyclic nucleotide binding homology domain, S4‐S5 linker, SF, N‐terminal EAG/PAS domain (1–135), S3‐S4 of VSD, and PAS, have been resolved individually. The structures of such hERG domains, along with the available crystal structures of other homologous K v channels, such as Shaker, K v AP, KcsA, Eag1,, and K v 1.2, have been useful to develop some significant insights into the hERG structure. The overall sequence similarities between hERG and different homologous structures are summarized in Table .…”

Section: Herg Channel: Structural Topologymentioning

confidence: 99%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

100

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Drug-induced blockade of human ether-a-go-go-related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off-target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure-based models of hERG have been developed as a low-cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off-target interactions with hERG.

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Individual Ion Binding Sites in the K+ Channel Play Distinct Roles in C-type Inactivation and in Recovery from Inactivation

Cited by 41 publications

References 61 publications

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

Hysteresis of KcsA potassium channel's activation– deactivation gating is caused by structural changes at the channel’s selectivity filter

Crystal structure of an inactivated mutant mammalian voltage-gated K+ channel

Development of Safe Drugs: The hERG Challenge

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