8I5N

Rat Kir4.1 in complex with PIP2 and Lys05

Summary for 8I5N

• Entry DOI: 10.2210/pdb8i5n/pdb
• EMDB information: 35196
• Descriptor: ATP-sensitive inward rectifier potassium channel 10, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate (2 entities in total)
• Functional Keywords: kir4.1, ion channel, transport protein, membrane protein
• Biological source: Rattus norvegicus (Norway rat)
• Total number of polymer chains: 4
• Total formula weight: 158153.16

Authors

Zhao, C.,Guo, J. (deposition date: 2023-01-26, release date: 2024-02-28, Last modification date: 2024-11-06)

Primary citation

Zhou, X.,Zhao, C.,Xu, H.,Xu, Y.,Zhan, L.,Wang, P.,He, J.,Lu, T.,Gu, Y.,Yang, Y.,Xu, C.,Chen, Y.,Liu, Y.,Zeng, Y.,Tian, F.,Chen, Q.,Xie, X.,Liu, J.,Hu, H.,Li, J.,Zheng, Y.,Guo, J.,Gao, Z.
Pharmacological inhibition of Kir4.1 evokes rapid-onset antidepressant responses.
Nat.Chem.Biol., 20:857-866, 2024

PubMed Abstract: Major depressive disorder, a prevalent and severe psychiatric condition, necessitates development of new and fast-acting antidepressants. Genetic suppression of astrocytic inwardly rectifying potassium channel 4.1 (Kir4.1) in the lateral habenula ameliorates depression-like phenotypes in mice. However, Kir4.1 remains an elusive drug target for depression. Here, we discovered a series of Kir4.1 inhibitors through high-throughput screening. Lys05, the most potent one thus far, effectively suppressed native Kir4.1 channels while displaying high selectivity against established targets for rapid-onset antidepressants. Cryogenic-electron microscopy structures combined with electrophysiological characterizations revealed Lys05 directly binds in the central cavity of Kir4.1. Notably, a single dose of Lys05 reversed the Kir4.1-driven depression-like phenotype and exerted rapid-onset (as early as 1 hour) antidepressant actions in multiple canonical depression rodent models with efficacy comparable to that of (S)-ketamine. Overall, we provided a proof of concept that Kir4.1 is a promising target for rapid-onset antidepressant effects.

PubMed: 38355723
DOI: 10.1038/s41589-024-01555-y

Experimental method

ELECTRON MICROSCOPY (2.85 Å)