K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site

Lolicato, Marco; Arrigoni, Cristina; Mori, Takeo; Sekioka, Yoko; Bryant, Clifford; Clark, Kimberly A.; Minor, Daniel L.

doi:10.1038/nature22988

Cited by 166 publications

(311 citation statements)

References 54 publications

(134 reference statements)

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“…Crystal structures are also now available for these three channels in multiple conformations (29)(30)(31)(32); thus, they provide an excellent opportunity to investigate the molecular mechanisms underlying mechanosensitivity in eukaryotic ion channels.…”

Section: Significancementioning

confidence: 99%

Asymmetric mechanosensitivity in a eukaryotic ion channel

Clausen

Jarerattanachat

Carpenter

et al. 2017

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

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Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian twopore domain (K2P) K + channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.any forms of sensory perception in higher organisms depend on the rapid conversion of mechanical and physical stimuli into the electrochemical language of nerve and muscle cells (1). These transduction mechanisms often involve "mechanosensitive" (MS) ion channels that are able to rapidly convert physicomechanical stimuli into the electrical signals required for complex physiological responses (e.g., touch, pain, hearing, proprioception), as well those mechanical signals that play key roles in development and cell-cell communication (2). The enormous complexity and diversity of these sensory responses suggests that a variety of molecular mechanisms are likely responsible; for example, while some channels are regulated via physical coupling to proteins of the cytoskeleton and/or cell matrix, others respond directly to changes in lipid membrane tension (3). The precise structural and physical mechanisms underlying these processes remain poorly understood, however (4-6).Our current understanding of how membrane tension directly regulates ion channel gating is largely derived from studies of prokaryotic MS ion channels involved in the control of bacterial turgor pressure (7,8). The open state of these MS channels has a larger cross-sectional area than the closed state within the membrane, and stretch-induced changes in the forces within the bilayer stabilize the expanded open-state conformation. This is commonly referred to as the force-from-lipid principle of mechanosensitivity (9). Similar physical principles are thought to regulate many eukaryotic MS channels (5, 10).Typically, the functional activity of MS ion channels is examined in pipette-based patch-clamp recordings in which negative or positive pressures are used to alter bilayer tension. These pressure changes stretch the membrane to alter the lateral pressure profile, the complex profile of forces that vary with location acro...

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Section: Significancementioning

confidence: 99%

Asymmetric mechanosensitivity in a eukaryotic ion channel

Clausen

Jarerattanachat

Carpenter

et al. 2017

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

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“…Apart from the crystallographically identified fluoxetine binding site provided by the side fenestrations, a completely different one was revealed in crystal structures of TREK-1 activated by two chemical compounds, evidencing a direct | 1601 ŞTERBULEAC tweaking of the C-type gate of the channel (Lolicato et al, 2017). The ligands, ML335 and ML402 (Figure 3a), were shown to bind in a cryptic modulator pocket located behind the SF and in between the P1/M4 interface ( Figure 3b).…”

Section: Recent Crystal Structures Revealed a Novel Cryptic Activatmentioning

confidence: 96%

“…Upon binding, the activators induced particular conformations of F134, K271, and W275 (compared to the apo structure) by strongly interacting with their side chains, while the bulkier ML335 additionally contacted H126, S131, N147, A259, and G260. Functional evidence that the compounds do alter the SF gate was observed (Lolicato et al, 2017), as their application caused a loss of outward rectification, rendering a "leak" mode in similar ways to most activatory physical and chemical stimuli . Similar to TREK-2 fenestration blockade, a dual-sided ligand binding was noticed, with two modulators per channel.…”

Section: Recent Crystal Structures Revealed a Novel Cryptic Activatmentioning

confidence: 99%

“…K2Ps also exhibit a domain-swapped chain connectivity (Niemeyer et al, 2016), which was not noticed in initial crystals and swaps the outer helices around the overall structure (Figure 1b,c). Additionally, the M4 helix manifests a kink in TWIK-1 (Miller & Long, 2012); this is not the case in TREK subfamily structures (Lolicato et al, 2017), where it resembles a long α-helix slightly curved toward the membrane (Figure 1b,c).…”

mentioning

confidence: 96%

“…AND THEIR INTERACTIONS WITH MODULATORS HAVE PARTICULAR FEATURES, TIGHTLY LINKED TO THEIR METABOLIC PROPERTIES 2.1 | Chemical modulation by fluoxetine and its derivatives and its close ties to gating and metabolic modulation of TREK subfamily channels 2.1.1 | Crystal structures revealed the molecular action site of fluoxetine derivatives, as distinguishable TREK inhibitors From the 15-membered human K2P family, the distinguishable polymodal channels comprising the TREK subfamily (TREK-1, TREK-2, and TRAAK) received particular attention, allowing ample observations about their cellular roles, gating, and interaction with chemical compounds. Important structural and functional evidence came from crystal structures of TREK and TRAAK channels (Brohawn, Campbell, & MacKinnon, 2014;Brohawn et al, 2012;Dong et al, 2015;Lolicato et al, 2017Lolicato et al, , 2014, which allowed an improved understanding of the fenestration dynamic state and molecular characteristics of interactions with modulators. The K2P gating processes are being constantly elucidated and (TREK-2)-ligand crystal structures demonstrated how the side fenestrations provide a quasi-hydrophobic binding site for blockers.…”

mentioning

confidence: 99%

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Molecular determinants of chemical modulation of two‐pore domain potassium channels

Șterbuleac

2019

Chem Biol Drug Des

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The K+ ion channels comprising the two‐pore domain (K2P) family have specific biophysical roles in generating the critical regulatory K+ current. Ion flow through K2P channels and, implicitly, channel regulation is mediated by diverse metabolic and physical inputs such as mechanical stimulation, interaction with lipids or endogenous regulators, intra‐ or extracellular pH, and phosphorylation, while their function can be finely tuned by chemical compounds. In the latter category, some drug–channel interactions can lead to side effects or have clinical action, while identifying novel chemical modulators of K2Ps is an area of intense research. Due to their cellular and therapeutic importance, much attention was turned to these channels in recent years and several experimental approaches have pinpointed the molecular determinants of K2P chemical modulation. Given their unique structural features and properties, chemical modulators act on K2P channels in multiple and diverse ways. In this review, the particularities of K2P modulation by chemical compounds, such as binding modality, affinity, or position, are identified, synthesized, and linked to structural and functional properties in order to refer to how activators and blockers modify channel function and vice versa, focusing on specificity related to protein structure (and its modification) and cross‐linking information among different subfamilies.

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Integration of Cation–π Interactions with Polyphenols for Super‐Hydrophilic Coatings

Zhang

Geng

Gao

et al. 2022

Adv Materials Inter

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Inspired by natural channels, graphene oxide membrane has been used to separate metals or solvents due to the different affinity between aromatic group and metal ions. [6] In addition, cation-π interactions have been used for the engineering underwater adhesive materials. [7] Mussel-inspired chemistry has demonstrated its versatility for multifunctional coatings based on the oxidized poly merization of dopamine (DA) and noncovalent interactions. [8] The cation-π interaction is one of the primary forces for the intermolecular assembly of DA, which is indicated by the formation and disassembly of the polydopamine (PDA) coatings at different pH. [9] The disassembled PDA coatings could reassemble into films in the presence of cation (e.g., K + ) for surface coatings, where cation types significantly influence the strength of cation-π interactions. In addition, the structure of aromatic groups also affects the strength of cation-π interactions, which is verified by detecting the adhesion force of polymers with aromatic side groups and poly-L-lysine. [10] Compared to DA, polyphenols (e.g., tannic acid, TA) have been demonstrated their superiority to functionalize substrates with colorless coatings or coordinate with metal ions for the engineering of films and particles. [11] However, the integration of cation-π interactions with polyphenols is rarely reported for surface functionalization.Herein, we report a facile approach for the engineering of super-hydrophilic coatings via the integration of cation-π interactions with polyphenols and investigate the effect of the types of cations and polyphenols on the hydrophilicity and stability of the coatings. As a result, coatings obtained from TA and tetramethylammonium (TMA) demonstrate super-hydrophilic property, which can be resistant against acid (pH 3) and alkali (pH 14). The polyphenol coatings based on cation-π interactions also show their superiority for oil-water separation, self-cleaning, and anti-foggy applications. The phenolic coatings based on the integration of cation-π interactions provide a promising strategy for surface engineering and functionalization. Results and DiscussionTo investigate the influence of pyrogallol and catechol on the cation-π interactions, TA and DA were used as the electron-rich π agents to bind cations (i.e., Na + and K + ) for copper mesh coatings (denoted as DA, DA-Na, DA-K, TA, TA-Na, and TA-K copper meshes). Scanning electron microscopy (SEM) images showed Cation-π interaction is one of the most important noncovalent interactions found in biosystems, which has attracted great interests for the engineering of functional materials. In this work, one-step assembly of super-hydrophilic coatings via surface modification with polyphenols and cations is reported based on cation-π interactions. Hydrophilicity of surface coatings is tunable by the variation of cations based on the different affinity between polyphenols and cations. Copper meshes coated with tannic acid and tetramethylammonium demonstrate super-hydrophilicity and high stab...

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K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site

Cited by 166 publications

References 54 publications

Asymmetric mechanosensitivity in a eukaryotic ion channel

Asymmetric mechanosensitivity in a eukaryotic ion channel

Molecular determinants of chemical modulation of two‐pore domain potassium channels

Integration of Cation–π Interactions with Polyphenols for Super‐Hydrophilic Coatings

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