Molecular basis for ligand activation of the human KCNQ2 channel

Li, Xiaoxiao; Zhang, Qiansen; Guo, Peipei; Fu, Jie; Mei, Lianghe; Lv, Dashuai; Wang, Jiangqin; Lai, Dongwu; Ye, Sheng; Yang, Huaiyu; Guo, Jiangtao

doi:10.1038/s41422-020-00410-8

Cited by 83 publications

(139 citation statements)

References 66 publications

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“…Here, we have suggested that Wu50 can bind in a fairly promiscuous drug pocket located in a cleft in the top of the VSD in different voltage-gated ion channels (Fig. 7, yellow; Ahuja et al, 2015;Li et al, 2013;Liin et al, 2018a;Peretz et al, 2010;Li et al, 2020). From here the negatively charged Wu50 could contribute to the negative G(V) shift by electrostatically attracting S4 charges to rotate S4 in the clockwise direction and favor activation.…”

Section: Discussionmentioning

confidence: 77%

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel

Ejneby

Gromova

Ottosson

et al. 2021

Journal of General Physiology

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Voltage-gated potassium (KV) channels can be opened by negatively charged resin acids and their derivatives. These resin acids have been proposed to attract the positively charged voltage-sensor helix (S4) toward the extracellular side of the membrane by binding to a pocket located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. By contrast to this proposed mechanism, neutralization of the top gating charge of the Shaker KV channel increased resin-acid–induced opening, suggesting other mechanisms and sites of action. Here, we explore the binding of two resin-acid derivatives, Wu50 and Wu161, to the activated/open state of the Shaker KV channel by a combination of in silico docking, molecular dynamics simulations, and electrophysiology of mutated channels. We identified three potential resin-acid–binding sites around S4: (1) the S3/S4 site previously suggested, in which positively charged residues introduced at the top of S4 are critical to keep the compound bound, (2) a site in the cleft between S4 and the pore domain (S4/pore site), in which a tryptophan at the top of S6 and the top gating charge of S4 keeps the compound bound, and (3) a site located on the extracellular side of the voltage-sensor domain, in a cleft formed by S1–S4 (the top-VSD site). The multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation make the effect of resin-acid derivatives on channel function intricate. The propensity of a specific resin acid to activate and open a voltage-gated channel likely depends on its exact binding dynamics and the types of interactions it can form with the protein in a state-specific manner.

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Section: Discussionmentioning

confidence: 77%

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel

Ejneby

Gromova

Ottosson

et al. 2021

Journal of General Physiology

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“…Lu AG00563 displays similar electrophysiological behavior to retigabine, which is a potentiator inducing a negative shift in the required activation voltage. The structure of Retigabine bound to Kv7.2 (Li et al, 2021b) and Kv7.4 (Li et al, 2021a) was recently solved and shows that the binding site of the compound is located next to the PD between S5 from one subunit and S6 from the neighboring subunit (Fig. 4B).…”

Section: A Novel Kv Potentiator-binding Sitementioning

confidence: 99%

Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 reveal a novel binding site for positive modulators

Botte¹,

Huber²,

Bucher³

et al. 2021

Preprint

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Kv3 ion-channels constitute a class of functionally distinct voltage gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders.

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“…The 3D structure of the rat Kv7.2 channel has been obtained by homology with the human KCNQ2 protein in apo state (49). The amino acid sequence of rat Kv7.…”

Section: Molecular Modelingmentioning

confidence: 99%

Long-lasting reduction of intrinsic excitability in O-LM interneurons is mediated by endocannabinoid-dependent up-regulation of Kv7 channels

Incontro

Sammari

Ankri

et al. 2021

Preprint

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KCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. The physiology of Kv7 channels is well characterized today but the precise contribution of these channels to neuronal plasticity is still unknown. Here, we show that Kv7 channel activity is up-regulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons, thus resulting in a synergistic long-term depression of intrinsic neuronal excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for their induction. Molecular modeling shows strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons.

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Molecular basis for ligand activation of the human KCNQ2 channel

Cited by 83 publications

References 66 publications

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel

Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel

Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 reveal a novel binding site for positive modulators

Long-lasting reduction of intrinsic excitability in O-LM interneurons is mediated by endocannabinoid-dependent up-regulation of Kv7 channels

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