8qz2

Crystal structure of human two pore domain potassium ion channel TREK-2 (K2P10.1) in complex with an inhibitory nanobody (Nb61)

spinqualitylabelsall models 8qz2, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8qz2 is a 3 chain structure with sequence from Homo sapiens and Lama glama. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.5Å Ligands: K Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KCNKA_HUMAN Outward rectifying potassium channel. Produces rapidly activating and non-inactivating outward rectifier K(+) currents. Activated by arachidonic acid and other naturally occurring unsaturated free fatty acids. Publication Abstract from PubMed 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. Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation.,Rodstrom KEJ, Cloake A, Sormann J, Baronina A, Smith KHM, Pike ACW, Ang J, Proks P, Schewe M, Holland-Kaye I, Bushell SR, Elliott J, Pardon E, Baukrowitz T, Owens RJ, Newstead S, Steyaert J, Carpenter EP, Tucker SJ Nat Commun. 2024 May 16;15(1):4173. doi: 10.1038/s41467-024-48536-2. PMID:38755204 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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