6rv4

Crystal structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1) in a closed conformation with a bound inhibitor BAY 2341237Crystal structure of the human two pore domain potassium ion channel TASK-1 (K2P3.1) in a closed conformation with a bound inhibitor BAY 2341237

Structural highlights 6rv4 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , Gene: KCNK3, TASK, TASK1 (HUMAN) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [KCNK3_HUMAN] Heritable pulmonary arterial hypertension. The disease is caused by mutations affecting the gene represented in this entry. Function [KCNK3_HUMAN] pH-dependent, voltage-insensitive, background potassium channel protein. Rectification direction results from potassium ion concentration on either side of the membrane. Acts as an outward rectifier when external potassium concentration is low. When external potassium concentration is high, current is inward. Publication Abstract from PubMed TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K2P channels regulate the resting membrane potential, providing background K(+) currents controlled by numerous physiological stimuli(12-15). Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below; however, the K2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an 'X-gate'-created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((243)VLRFMT(248)) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders. A lower X-gate in TASK channels traps inhibitors within the vestibule.,Rodstrom KEJ, Kiper AK, Zhang W, Rinne S, Pike ACW, Goldstein M, Conrad LJ, Delbeck M, Hahn MG, Meier H, Platzk M, Quigley A, Speedman D, Shrestha L, Mukhopadhyay SMM, Burgess-Brown NA, Tucker SJ, Muller T, Decher N, Carpenter EP Nature. 2020 Jun;582(7812):443-447. doi: 10.1038/s41586-020-2250-8. Epub 2020 Apr, 29. PMID:32499642 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Potassium channel 3D structures

spinqualitylabelsall models 6rv4, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image