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- PDB-7w48: Crystal structure of the gastric proton pump complexed with PF-03... -
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Basic information
Entry | Database: PDB / ID: 7w48 | ||||||
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Title | Crystal structure of the gastric proton pump complexed with PF-03716556 | ||||||
![]() | (Potassium-transporting ATPase ...) x 2 | ||||||
![]() | HYDROLASE / Cation pump / P-type ATPase / gastric / proton pump / membrane protein / P-CAB | ||||||
Function / homology | ![]() H+/K+-exchanging ATPase / potassium:proton exchanging ATPase complex / P-type potassium:proton transporter activity / Ion transport by P-type ATPases / P-type sodium:potassium-exchanging transporter activity / sodium:potassium-exchanging ATPase complex / sodium ion export across plasma membrane / intracellular potassium ion homeostasis / intracellular sodium ion homeostasis / potassium ion import across plasma membrane ...H+/K+-exchanging ATPase / potassium:proton exchanging ATPase complex / P-type potassium:proton transporter activity / Ion transport by P-type ATPases / P-type sodium:potassium-exchanging transporter activity / sodium:potassium-exchanging ATPase complex / sodium ion export across plasma membrane / intracellular potassium ion homeostasis / intracellular sodium ion homeostasis / potassium ion import across plasma membrane / potassium ion binding / ATPase activator activity / potassium ion transmembrane transport / proton transmembrane transport / cell adhesion / apical plasma membrane / magnesium ion binding / ATP hydrolysis activity / ATP binding / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Abe, K. / Tanaka, S. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural Basis for Binding of Potassium-Competitive Acid Blockers to the Gastric Proton Pump. Authors: Saki Tanaka / Mikio Morita / Tatsuya Yamagishi / Hridya Valia Madapally / Kenichi Hayashida / Himanshu Khandelia / Christoph Gerle / Hideki Shigematsu / Atsunori Oshima / Kazuhiro Abe / ![]() ![]() Abstract: As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid- ...As specific inhibitors of the gastric proton pump, responsible for gastric acidification, K-competitive acid blockers (P-CABs) have recently been utilized in the clinical treatment of gastric acid-related diseases in Asia. However, as these compounds have been developed based on phenotypic screening, their detailed binding poses are unknown. We show crystal and cryo-EM structures of the gastric proton pump in complex with four different P-CABs, tegoprazan, soraprazan, PF-03716556 and revaprazan, at resolutions reaching 2.8 Å. The structures describe molecular details of their interactions and are supported by functional analyses of mutations and molecular dynamics simulations. We reveal that revaprazan has a novel binding mode in which its tetrahydroisoquinoline moiety binds deep in the cation transport conduit. The mechanism of action of these P-CABs can now be evaluated at the molecular level, which will facilitate the rational development and improvement of currently available P-CABs to provide better treatment of acid-related gastrointestinal diseases. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 324 KB | Display | ![]() |
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PDB format | ![]() | 207.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.1 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 47 KB | Display | |
Data in CIF | ![]() | 62.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7w47C ![]() 7w49C ![]() 7w4aC ![]() 5ylvS S: Starting model for refinement C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Unit cell |
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Components
-Potassium-transporting ATPase ... , 2 types, 2 molecules AB
#1: Protein | Mass: 114456.734 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 33113.844 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
-Sugars , 1 types, 3 molecules ![](data/chem/img/NAG.gif)
#7: Sugar |
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-Non-polymers , 5 types, 8 molecules ![](data/chem/img/MG.gif)
![](data/chem/img/CE1.gif)
![](data/chem/img/RB.gif)
![](data/chem/img/8BZ.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/CE1.gif)
![](data/chem/img/RB.gif)
![](data/chem/img/8BZ.gif)
![](data/chem/img/PCW.gif)
#3: Chemical | ChemComp-MG / | ||||||
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#4: Chemical | #5: Chemical | #6: Chemical | ChemComp-8BZ / | #8: Chemical | ChemComp-PCW / | |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 3.96 Å3/Da / Density % sol: 68.92 % |
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Crystal grow | Temperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5 Details: 10% glycerol, 0.2 M RbCl, 20% PEG2000MME, 3% tert-BuOH, 5 mM beta-MeSH |
-Data collection
Diffraction | Mean temperature: 77 K / Serial crystal experiment: N |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 12, 2018 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 3.5→48.18 Å / Num. obs: 30417 / % possible obs: 75.31 % / Redundancy: 6.7 % / Biso Wilson estimate: 83.51 Å2 / CC1/2: 0.998 / Net I/σ(I): 5.55 |
Reflection shell | Resolution: 3.5→3.626 Å / Num. unique obs: 556 / CC1/2: 0.318 |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 5ylv Resolution: 3.5→48.18 Å / SU ML: 0.5583 / Cross valid method: FREE R-VALUE / σ(F): 1.31 / Phase error: 32.2116 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 84.28 Å2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.5→48.18 Å
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Refine LS restraints |
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LS refinement shell |
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