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Resin-acid derivati...
Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel
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- Silverå Ejneby, Malin (författare)
- Linköpings universitet,Medicinska fakulteten,Avdelningen för neurobiologi
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- Gromova, Arina (författare)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden
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- Ottosson, Nina (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Borg, Stina (författare)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden
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- Estrada Mondragón, Argel (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Yazdi, Samira (författare)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden
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- Apostolakis, Panagiotis (författare)
- KTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden
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- Elinder, Fredrik (författare)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Delemotte, Lucie (författare)
- KTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden
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(creator_code:org_t)
- 2021-03-08
- 2021
- Engelska.
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Ingår i: The Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 153:4
- Relaterad länk:
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https://doi.org/10.1...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Voltage-gated potassium (K-V) 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
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- art (ämneskategori)
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