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Open data
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Basic information
Entry | Database: PDB / ID: 8jmn | ||||||
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Title | Cryo-EM structure of the gastric proton pump with bound DQ-21 | ||||||
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![]() | MEMBRANE PROTEIN / P-type ATPase / P2-type ATPase | ||||||
Function / homology | ![]() regulation of proton transport / pH reduction / potassium:proton exchanging ATPase complex / P-type potassium:proton transporter activity / Ion transport by P-type ATPases / 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 ...regulation of proton transport / pH reduction / potassium:proton exchanging ATPase complex / P-type potassium:proton transporter activity / Ion transport by P-type ATPases / 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 / ATPase activator activity / potassium ion transmembrane transport / proton transmembrane transport / cell adhesion / apical plasma membrane / response to xenobiotic stimulus / magnesium ion binding / ATP hydrolysis activity / ATP binding Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.26 Å | ||||||
![]() | Abe, K. / Yokoshima, S. / Yoshimori, A. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Deep learning driven de novo drug design based on gastric proton pump structures. Authors: Kazuhiro Abe / Mami Ozako / Miki Inukai / Yoe Matsuyuki / Shinnosuke Kitayama / Chisato Kanai / Chiaki Nagai / Chai C Gopalasingam / Christoph Gerle / Hideki Shigematsu / Nariyoshi Umekubo / ...Authors: Kazuhiro Abe / Mami Ozako / Miki Inukai / Yoe Matsuyuki / Shinnosuke Kitayama / Chisato Kanai / Chiaki Nagai / Chai C Gopalasingam / Christoph Gerle / Hideki Shigematsu / Nariyoshi Umekubo / Satoshi Yokoshima / Atsushi Yoshimori / ![]() Abstract: Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. ...Existing drugs often suffer in their effectiveness due to detrimental side effects, low binding affinity or pharmacokinetic problems. This may be overcome by the development of distinct compounds. Here, we exploit the rich structural basis of drug-bound gastric proton pump to develop compounds with strong inhibitory potency, employing a combinatorial approach utilizing deep generative models for de novo drug design with organic synthesis and cryo-EM structural analysis. Candidate compounds that satisfy pharmacophores defined in the drug-bound proton pump structures, were designed in silico utilizing our deep generative models, a workflow termed Deep Quartet. Several candidates were synthesized and screened according to their inhibition potencies in vitro, and their binding poses were in turn identified by cryo-EM. Structures reaching up to 2.10 Å resolution allowed us to evaluate and re-design compound structures, heralding the most potent compound in this study, DQ-18 (N-methyl-4-((2-(benzyloxy)-5-chlorobenzyl)oxy)benzylamine), which shows a K value of 47.6 nM. Further high-resolution cryo-EM analysis at 2.08 Å resolution unambiguously determined the DQ-18 binding pose. Our integrated approach offers a framework for structure-based de novo drug development based on the desired pharmacophores within the protein structure. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 298.1 KB | Display | ![]() |
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PDB format | ![]() | 214.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 36424MC ![]() 8ijvC ![]() 8ijwC ![]() 8ijxC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 114325.547 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)
#6: Sugar |
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-Non-polymers , 5 types, 381 molecules ![](data/chem/img/PCW.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/UOU.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/UOU.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/HOH.gif)
#3: Chemical | ChemComp-PCW / #4: Chemical | ChemComp-MG / | #5: Chemical | ChemComp-UOU / | #7: Chemical | ChemComp-CLR / | #8: Water | ChemComp-HOH / | |
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-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 |
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Sample preparation
Component | Name: hetero dimer of alpha and beta subunit / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.135 MDa / Experimental value: YES |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 6.5 |
Specimen | Conc.: 8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Microscopy | Model: JEOL CRYO ARM 300 |
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Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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Particle selection | Num. of particles selected: 2230909 |
3D reconstruction | Resolution: 2.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 599919 / Symmetry type: POINT |
Refinement | Cross valid method: NONE |