Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity

Heusser, Stephanie A.; Lycksell, Marie; Wang, Xueqing; McComas, Sarah; Howard, Rebecca J.; Lindahl, Erik

doi:10.1073/pnas.1809650115

Cited by 25 publications

(27 citation statements)

References 54 publications

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“…One explanation would be that the VA-binding site identified in our study represents only one of a subset of VA modulatory domains in the K2P family. Within the anesthetic mechanisms literature there are numerous examples of VA-responsive ion channels that feature multiple low-affinity anesthetic modulatory sites acting in a combinatorial fashion to produce a given output ( Fourati et al, 2018 ; Heusser et al, 2018 ; Woll et al, 2018 ; Hemmings et al, 2019 ). However, the location of the identified K2P VA-binding site at a position central to TM4 gating offers an alternative explanation.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic insights into volatile anesthetic modulation of K2P channels

Wague

Joseph

Woll

et al. 2020

eLife

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K2P potassium channels are known to be modulated by volatile anesthetic (VA) drugs and play important roles in clinically relevant effects that accompany general anesthesia. Here, we utilize a photoaffinity analog of the VA isoflurane to identify a VA-binding site in the TREK1 K2P channel. The functional importance of the identified site was validated by mutagenesis and biochemical modification. Molecular dynamics simulations of TREK1 in the presence of VA found multiple neighboring residues on TREK1 TM2, TM3, and TM4 that contribute to anesthetic binding. The identified VA-binding region contains residues that play roles in the mechanisms by which heat, mechanical stretch, and pharmacological modulators alter TREK1 channel activity and overlaps with positions found to modulate TASK K2P channel VA sensitivity. Our findings define molecular contacts that mediate VA binding to TREK1 channels and suggest a mechanistic basis to explain how K2P channels are modulated by VAs.

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Section: Discussionmentioning

confidence: 99%

Mechanistic insights into volatile anesthetic modulation of K2P channels

Wague

Joseph

Woll

et al. 2020

eLife

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“…Traditional structure-based drug design aims to optimize compounds that fit in and strongly bind to a well-defined pocket of a biomolecule. This work, together with recent developments (Heusser et al, 2018), show that membrane proteins may be druggable via binding of compounds in a state-dependent manner, in different binding sites with similar binding affinity, and via mechanisms involving the membrane (Ahuja et al, 2015;Lambert et al, 2003;Wang, 2011). The resin-acid derivatives studied in this work seem to possess all of these three properties.…”

Section: Advantages and Challenges Of Multi-site Drug Actionmentioning

confidence: 52%

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

Ejneby

Gromova

Ottosson

et al. 2020

Preprint

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Resin acids and their derivatives open voltage-gated potassium (KV) channels by attracting the positively charged voltage sensor helix of the channel (S4) towards the extracellular leaflet of the cellular membrane and thereby favoring gate opening. The resin acids have been proposed to primarily bind in a pocket in the periphery of the channel, located between the lipid-facing extracellular ends of the transmembrane segments S3 and S4. However, neutralization of the top gating charge of the Shaker KV channel unexpectedly increases the resin-acid induced opening, suggesting other mechanisms and possibly other sites of action.Here we explored the binding of two resin-acid derivatives, Wu50 and Wu161, to the Shaker KV channel by a combination of in-silico docking, molecular dynamics simulations, and electrophysiological study of mutated channels. We identified three potential resin-acid binding sites around the voltage sensor helix S4: (1) the S3/S4 site identified in our previous work, (2) a site located in the cleft between S4 and the pore domain (the S4/pore site), and (3) a site located at the extracellular side of the voltage-sensor domain in a cleft formed by S1-S4 (the top-VSD site). The presence of multiple binding sites around S4 and the anticipated helical-screw motion of the helix during activation makes the effect of resin acid derivatives on channel function intricate. The propensity of a specific resin acid to open/close a voltagegated channel likely depends on its exact binding pose and the types of interactions it can form with the protein in a state-specific manner.

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“…Traditional structure-based drug design aims to optimize compounds that fit in and strongly bind to a well-defined pocket of a biomolecule. This work, together with recent developments ( Heusser et al, 2018 ), shows that membrane proteins may be druggable via binding of compounds in a state-dependent manner, in different binding sites with similar binding affinity, and via mechanisms involving the membrane ( Ahuja et al, 2015 ; Lambert et al, 2003 ; Wang, 2011 ). The resin-acid derivatives studied in this work seem to possess all of these three properties.…”

Section: Discussionmentioning

confidence: 79%

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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Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity

Cited by 25 publications

References 54 publications

Mechanistic insights into volatile anesthetic modulation of K2P channels

Mechanistic insights into volatile anesthetic modulation of K2P channels

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

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

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