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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 ...

  • 2021-03-08
  • Rockefeller University Press,2021
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:kth-292606
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-292606URI
  • https://doi.org/10.1085/jgp.202012676DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-174771URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • QC 20210409
  • 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]
  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Gromova, ArinaKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u12gr154 (författare)
  • Ottosson, NinaLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)ninot92 (författare)
  • Borg, StinaKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1odynb9 (författare)
  • Estrada Mondragón, ArgelLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)arges08 (författare)
  • Yazdi, SamiraKTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1vx8y4q (författare)
  • Apostolakis, PanagiotisKTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u1yljwwu (författare)
  • Elinder, FredrikLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)freel71 (författare)
  • Delemotte, LucieKTH,Biofysik,Science for Life Laboratory, SciLifeLab,KTH Royal Inst Technol, Sweden(Swepub:kth)u15w0he7 (författare)
  • Linköpings universitetMedicinska fakulteten (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:The Journal of General Physiology: Rockefeller University Press153:40022-12951540-7748

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