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Structure paper

TitleSmall molecule modulation of the Drosophila Slo channel elucidated by cryo-EM.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 7164, Year 2021
Publish dateDec 9, 2021
AuthorsTobias Raisch / Andreas Brockmann / Ulrich Ebbinghaus-Kintscher / Jörg Freigang / Oliver Gutbrod / Jan Kubicek / Barbara Maertens / Oliver Hofnagel / Stefan Raunser /
PubMed AbstractSlowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca concentrations and are ...Slowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca concentrations and are important targets for insecticides and antiparasitic drugs. However, it is unknown how these compounds modulate ion translocation and whether there are insect-specific binding pockets. Here, we report structures of Drosophila Slo in the Ca-bound and Ca-free form and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. Whereas the architecture and gating mechanism of Slo channels are conserved, potential insect-specific binding pockets exist. Verruculogen inhibits K transport by blocking the Ca-induced activation signal and precludes K from entering the selectivity filter. Emodepside decreases the conductance by suboptimal K coordination and uncouples ion gating from Ca and voltage sensing. Our results expand the mechanistic understanding of Slo regulation and lay the foundation for the rational design of regulators of Slo and other voltage-gated ion channels.
External linksNat Commun / PubMed:34887422 / PubMed Central
MethodsEM (single particle)
Resolution2.38 - 2.73 Å
Structure data

13700

7pxe

EMDB-13700, PDB-7pxe:
Ca2+ bound Drosophila Slo channel
Method: EM (single particle) / Resolution: 2.38 Å

13701

7pxf

EMDB-13701, PDB-7pxf:
Ca2+ free Drosophila Slo channel
Method: EM (single particle) / Resolution: 2.68 Å

13702

7pxg

EMDB-13702, PDB-7pxg:
Verruculogen-bound Drosophila Slo channel
Method: EM (single particle) / Resolution: 2.73 Å

13703

7pxh

EMDB-13703, PDB-7pxh:
Emodepside-bound Drosophila Slo channel
Method: EM (single particle) / Resolution: 2.59 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-6PL:
(4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE / phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-K:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-8H5:
Verruculogen / toxin*YM

ChemComp-8I2:
(3~{S},6~{R},9~{S},12~{R},15~{S},18~{R},21~{S},24~{R})-4,6,10,16,18,22-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-12,24-bis[(4-morpholin-4-ylphenyl)methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octone / antiparasitic*YM

Source
  • drosophila melanogaster (fruit fly)
KeywordsTRANSPORT PROTEIN / Potassium transport / BK channel

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