5Y0B

PIG GASTRIC H+,K+ - ATPASE IN COMPLEX with BYK99

5Y0B の概要

• エントリーDOI: 10.2210/pdb5y0b/pdb
• EMDBエントリー: 6799
• 分子名称: Potassium-transporting ATPase alpha chain 1, Potassium-transporting ATPase subunit beta (2 entities in total)
• 機能のキーワード: ion pump, h+, k+-atpase, p-type atpase, membrane protein, hydrolase, e2, aluminium fluoride, atp-binding, hydrogen ion transport, ion transport, magnesium, membrane, metal-binding, nucleotide-binding, phosphoprotein, potassium, potassium transport, transmembrane, transport, disulfide bond, glycoprotein, signal-anchor
• 由来する生物種: Sus scrofa (Pig); 詳細
• 細胞内の位置: Cell membrane ; Multi-pass membrane protein : P19156; Cell membrane ; Single-pass type II membrane protein : P18434
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 147513.53

構造登録者

Abe, K.,Shimokawa, J.,Natio, M.,Munson, K.,Vagin, O.,Sachs, G.,Suzuki, H.,Tani, K.,Fujiyoshi, Y. (登録日: 2017-07-16, 公開日: 2017-08-09, 最終更新日: 2024-11-06)

主引用文献

Abe, K.,Shimokawa, J.,Naito, M.,Munson, K.,Vagin, O.,Sachs, G.,Suzuki, H.,Tani, K.,Fujiyoshi, Y.
The cryo-EM structure of gastric H(+),K(+)-ATPase with bound BYK99, a high-affinity member of K(+)-competitive, imidazo[1,2-a]pyridine inhibitors
Sci Rep, 7:6632-6632, 2017

PubMed Abstract: The gastric proton pump H,K-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H,K-ATPase at 6.5 Å resolution in the E2P state with bound BYK99, a potent P-CAB with a restricted ring structure. The BYK99 bound structure has an almost identical profile to that of a previously determined structure with bound SCH28080, the original P-CAB prototype, but is significantly different from the previously reported P-CAB-free form, illustrating a common conformational change is required for P-CAB binding. The shared conformational changes include a distinct movement of transmembrane helix 2 (M2), from its position in the previously reported P-CAB-free form, to a location proximal to the P-CAB binding site in the present BYK99-bound structure. Site-specific mutagenesis within M2 revealed that D137 and N138, which face the P-CAB binding site in our model, significantly affect the inhibition constant (K ) of P-CABs. We also found that A335 is likely to be near the bridging nitrogen at the restricted ring structure of the BYK99 inhibitor. These provide clues to elucidate the binding site parameters and mechanism of P-CAB inhibition of gastric acid secretion.

PubMed: 28747707
DOI: 10.1038/s41598-017-06698-8

実験手法

ELECTRON CRYSTALLOGRAPHY (6.5 Å)