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TitleExtracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 4173, Year 2024
Publish dateMay 16, 2024
AuthorsKarin E J Rödström / Alexander Cloake / Janina Sörmann / Agnese Baronina / Kathryn H M Smith / Ashley C W Pike / Jackie Ang / Peter Proks / Marcus Schewe / Ingelise Holland-Kaye / Simon R Bushell / Jenna Elliott / Els Pardon / Thomas Baukrowitz / Raymond J Owens / Simon Newstead / Jan Steyaert / Elisabeth P Carpenter / Stephen J Tucker /
PubMed AbstractPotassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic ...Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.
External linksNat Commun / PubMed:38755204 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.4 - 7.37 Å
Structure data

EMDB-19066: TREK2 in OGNG/CHS detergent micelle with biparatopic inhibitory nanobody Nb6158
Method: EM (single particle) / Resolution: 7.37 Å

PDB-8qz1:
Crystal structure of human two pore domain potassium ion channel TREK-2 (K2P10.1) in complex with a nanobody (Nb58)
Method: X-RAY DIFFRACTION / Resolution: 3.588 Å

PDB-8qz2:
Crystal structure of human two pore domain potassium ion channel TREK-2 (K2P10.1) in complex with an inhibitory nanobody (Nb61)
Method: X-RAY DIFFRACTION / Resolution: 3.5 Å

PDB-8qz3:
Crystal structure of human two pore domain potassium ion channel TREK-2 (K2P10.1) in complex with an activatory nanobody (Nb67)
Method: X-RAY DIFFRACTION / Resolution: 2.4 Å

PDB-8qz4:
Crystal structure of human two pore domain potassium ion channel TREK-2 (K2P10.1) in complex with an activatory nanobody (Nb76)
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

Chemicals

ChemComp-K:
Unknown entry

ChemComp-MPD:
(4S)-2-METHYL-2,4-PENTANEDIOL / precipitant*YM

ChemComp-HOH:
WATER

ChemComp-BA:
Unknown entry

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / Potassium ion channel / Nanobody / Structural Genomics / Structural Genomics Consortium / SGC

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