Biotechnology and Biological Sciences Research Council (BBSRC)
BB/T002018/1
United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)
BB/S008608/1
United Kingdom
Medical Research Council (MRC, United Kingdom)
MR/W017741/1
United Kingdom
Grenoble Instruct-ERIC Center (ISBG)
France
Research Foundation - Flanders (FWO)
Belgium
Wellcome Trust
106169/Z/14/Z
United Kingdom
Wellcome Trust
WT084655MA
United Kingdom
Wellcome Trust
102161/B/13/Z
United Kingdom
Citation
Journal: Nat Commun / Year: 2024 Title: Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation. Authors: Karin 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 ...Authors: Karin 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 / Abstract: 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 ...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.
A: Isoform B of Potassium channel subfamily K member 10 B: Isoform B of Potassium channel subfamily K member 10 C: Nanobody 58 D: Nanobody 58 hetero molecules
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