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Resin-acid derivati...
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Silverå Ejneby, MalinLinköpings universitet,Medicinska fakulteten,Avdelningen för neurobiologi
(författare)
Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel
- Artikel/kapitelEngelska2021
Förlag, utgivningsår, omfång ...
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2021-03-08
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Rockefeller University Press,2021
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:kth-292606
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-292606URI
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https://doi.org/10.1085/jgp.202012676DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-174771URI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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QC 20210409
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Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [20180404, 2018-04905]; Gustafsson Foundation, and Science for Life Laboratory; Swedish Brain Foundation [FO2019-0247]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [20180404]
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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.
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Biuppslag (personer, institutioner, konferenser, titlar ...)
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Gromova, ArinaKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u12gr154
(författare)
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Ottosson, NinaLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)ninot92
(författare)
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Borg, StinaKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1odynb9
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Estrada Mondragón, ArgelLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)arges08
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Yazdi, SamiraKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1vx8y4q
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Apostolakis, PanagiotisKTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1yljwwu
(författare)
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Elinder, FredrikLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)freel71
(författare)
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Delemotte, LucieKTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u15w0he7
(författare)
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Linköpings universitetMedicinska fakulteten
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:The Journal of General Physiology: Rockefeller University Press153:40022-12951540-7748
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