6cq9

K2P2.1(TREK-1):ML402 complex

spinqualitylabelsall models 6cq9, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6cq9 is a 2 chain structure with sequence from Mus musculus. This structure supersedes the now removed PDB entry 5vkp. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: 16C, CD, K, Q5F, R16 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KCNK2_MOUSE Ion channel that contributes to passive transmembrane potassium transport. Reversibly converts between a voltage-insensitive potassium leak channel and a voltage-dependent outward rectifying potassium channel in a phosphorylation-dependent manner. In astrocytes, forms mostly heterodimeric potassium channels with KCNK1, with only a minor proportion of functional channels containing homodimeric KCNK2 (PubMed:24496152). In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1 (PubMed:24496152). Publication Abstract from PubMed Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-pi interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K2P selectivity filter gating. K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site.,Lolicato M, Arrigoni C, Mori T, Sekioka Y, Bryant C, Clark KA, Minor DL Jr Nature. 2017 Jul 20;547(7663):364-368. doi: 10.1038/nature22988. Epub 2017 Jul, 10. PMID:28693035 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Potassium channel 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA