Journal: Sci Rep / Year: 2017 Title: 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. Authors: Kazuhiro Abe / Jun Shimokawa / Mao Naito / Keith Munson / Olga Vagin / George Sachs / Hiroshi Suzuki / Kazutoshi Tani / Yoshinori Fujiyoshi / 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 ...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.
History
Deposition
Jul 16, 2017
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Header (metadata) release
Aug 9, 2017
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Map release
Aug 9, 2017
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Update
Aug 9, 2017
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Current status
Aug 9, 2017
Processing site: PDBj / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Film or detector model: KODAK SO-163 FILM / Average electron dose: 8.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron optics
Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Camera length: 1500 mm
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Image processing
Final reconstruction
Resolution.type: BY AUTHOR / Resolution: 6.5 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Software - Name: MRC
Crystal parameters
Unit cell - A: 142.6 Å / Unit cell - B: 112.0 Å / Unit cell - C: 320 Å / Unit cell - C sampling length: 320 Å / Unit cell - γ: 90 ° / Plane group: P 2 21 21
CTF correction
Software - Name: MRC
Crystallography statistics
Number intensities measured: 59212 / Number structure factors: 4974 / Fourier space coverage: 47.1 / R sym: 0.469 / R merge: 0.469 / Overall phase error: 33.1 / Overall phase residual: 33.1 / Phase error rejection criteria: 0 / High resolution: 6.5 Å / Shell - Shell ID: 1 / Shell - High resolution: 6.5 Å / Shell - Low resolution: 200.0 Å / Shell - Number structure factors: 4974 / Shell - Phase residual: 33.1 / Shell - Fourier space coverage: 47.1 / Shell - Multiplicity: 11.9
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Atomic model buiding 1
Refinement
Space: REAL / Protocol: RIGID BODY FIT / Target criteria: correlation coefficient
Output model
PDB-5y0b: PIG GASTRIC H+,K+ - ATPASE IN COMPLEX with BYK99
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