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Yorodumi- PDB-7w4a: Cryo-EM structure of the gastric proton pump complexed with revaprazan -
+Open data
-Basic information
Entry | Database: PDB / ID: 7w4a | ||||||
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Title | Cryo-EM structure of the gastric proton pump complexed with revaprazan | ||||||
Components | (Potassium-transporting ATPase ...) x 2 | ||||||
Keywords | HYDROLASE / Cation pump / P-type ATPase / gastric / proton pump / membrane protein / P-CAB | ||||||
Function / homology | Function and homology information 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 | Sus scrofa (pig) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å | ||||||
Authors | Abe, K. / Tanaka, S. / Morita, M. / Yamagishi, T. | ||||||
Funding support | Japan, 1items
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Citation | Journal: J Med Chem / Year: 2022 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
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7w4a.cif.gz | 249.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7w4a.ent.gz | 192.3 KB | Display | PDB format |
PDBx/mmJSON format | 7w4a.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7w4a_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 7w4a_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 7w4a_validation.xml.gz | 49.7 KB | Display | |
Data in CIF | 7w4a_validation.cif.gz | 73.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/w4/7w4a ftp://data.pdbj.org/pub/pdb/validation_reports/w4/7w4a | HTTPS FTP |
-Related structure data
Related structure data | 32299MC 7w47C 7w48C 7w49C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | |
EM raw data | EMPIAR-11057 (Title: Cryo-EM structure of the gastric proton pump complexed with revaprazan Data size: 2.1 TB Data #1: K3 movies for the gastric proton pump complexed with revaprazan - Movies_5 [micrographs - multiframe] Data #2: K3 movies for the gastric proton pump complexed with revaprazan - Movies_7 [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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1 |
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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.) Sus scrofa (pig) / Gene: ATP4A / Production host: Homo sapiens (human) / References: UniProt: P19156, H+/K+-exchanging ATPase |
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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.) Sus scrofa (pig) / Gene: ATP4B / Production host: Homo sapiens (human) / References: UniProt: P18434 |
-Sugars , 1 types, 3 molecules
#6: Sugar |
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-Non-polymers , 5 types, 16 molecules
#3: Chemical | ChemComp-8CK / |
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#4: Chemical | ChemComp-NA / |
#5: Chemical | ChemComp-MG / |
#7: Chemical | ChemComp-PCW / |
#8: Water | ChemComp-HOH / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: gastric proton pump / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.135 MDa / Experimental value: YES |
Source (natural) | Organism: Sus scrofa (pig) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 6.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Microscopy | Model: JEOL CRYO ARM 300 |
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Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 48 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 44404 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 56.14 Å2 | ||||||||||||||||||||||||
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