8UF6

Structure of Trek-1(K2P2.1) with ML336

Summary for 8UF6

• Entry DOI: 10.2210/pdb8uf6/pdb
• Related: 8UE2 8UE9 8UEC
• Descriptor: Potassium channel subfamily K member 2, HEXADECANE, N-[(2,4-dichlorophenyl)methyl]-4-propanamidobenzamide, ... (10 entities in total)
• Functional Keywords: membrane preotein, ml335, trek1, trek-1, malemide, trek-1 ligand, crystal, trans-membrane protein, transmembrane protein, k2p, two pore potassium channel, potassium channel, kcnk2, potassium channel subfamily k member 2, membrane protein, ml336, lh9
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 66509.44

Authors

Lolicato, M.,Mondal, A.,Minor, D.L. (deposition date: 2023-10-03, release date: 2024-06-26, Last modification date: 2025-01-08)

Primary citation

Deal, P.E.,Lee, H.,Mondal, A.,Lolicato, M.,Mendonca, P.R.F.,Black, H.,Jang, S.,El-Hilali, X.,Bryant, C.,Isacoff, E.Y.,Renslo, A.R.,Minor Jr., D.L.
Development of covalent chemogenetic K 2P channel activators.
Cell Chem Biol, 31:1305-1323.e9, 2024

PubMed Abstract: K potassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K function remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (covalent activation of TREK family K channels to clamp membrane potential) that leverages the discovery of a K modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. We show that CATKLAMP can be used to probe fundamental aspects of K function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a means to alter K channel activity that should facilitate molecular and systems level studies of K function and enable the search for new K modulators.

PubMed: 39029456
DOI: 10.1016/j.chembiol.2024.06.006

Experimental method

X-RAY DIFFRACTION (2.9 Å)