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- EMDB-32299: Cryo-EM structure of the gastric proton pump complexed with revaprazan -

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Basic information

Entry
Database: EMDB / ID: EMD-32299
TitleCryo-EM structure of the gastric proton pump complexed with revaprazan
Map data
Sample
  • Complex: gastric proton pump
    • Protein or peptide: Potassium-transporting ATPase alpha chain 1
    • Protein or peptide: Potassium-transporting ATPase subunit beta
  • Ligand: N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidin-2-amine
  • Ligand: SODIUM IONSodium
  • Ligand: MAGNESIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: water
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 / ATPase activator activity / potassium ion binding / 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
Gastric H+/K+-transporter P-type ATPase, N-terminal / Gastric H+/K+-ATPase, N terminal domain / Sodium/potassium-transporting ATPase subunit beta / Sodium/potassium-transporting ATPase subunit beta superfamily / Sodium / potassium ATPase beta chain / Sodium and potassium ATPases beta subunits signature 1. / Sodium and potassium ATPases beta subunits signature 2. / P-type ATPase subfamily IIC, subunit alpha / Cation-transporting P-type ATPase, C-terminal / Cation transporting ATPase, C-terminus ...Gastric H+/K+-transporter P-type ATPase, N-terminal / Gastric H+/K+-ATPase, N terminal domain / Sodium/potassium-transporting ATPase subunit beta / Sodium/potassium-transporting ATPase subunit beta superfamily / Sodium / potassium ATPase beta chain / Sodium and potassium ATPases beta subunits signature 1. / Sodium and potassium ATPases beta subunits signature 2. / P-type ATPase subfamily IIC, subunit alpha / Cation-transporting P-type ATPase, C-terminal / Cation transporting ATPase, C-terminus / Cation transporter/ATPase, N-terminus / Cation-transporting P-type ATPase, N-terminal / Cation transporter/ATPase, N-terminus / Cation transport ATPase (P-type) / E1-E2 ATPase / P-type ATPase, haloacid dehalogenase domain / P-type ATPase, phosphorylation site / P-type ATPase, cytoplasmic domain N / E1-E2 ATPases phosphorylation site. / P-type ATPase, A domain superfamily / P-type ATPase / P-type ATPase, transmembrane domain superfamily / haloacid dehalogenase-like hydrolase / HAD superfamily / HAD-like superfamily
Similarity search - Domain/homology
Potassium-transporting ATPase subunit beta / Potassium-transporting ATPase alpha chain 1
Similarity search - Component
Biological speciesSus scrofa (pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsAbe K / Tanaka S / Morita M / Yamagishi T
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H02426 Japan
CitationJournal: 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
DepositionNov 26, 2021-
Header (metadata) releaseMar 2, 2022-
Map releaseMar 2, 2022-
UpdateJul 20, 2022-
Current statusJul 20, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.027
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.027
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7w4a
  • Surface level: 0.027
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_32299.png

Downloads & links

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Map

FileDownload / File: emd_32299.map.gz / Format: CCP4 / Size: 76.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.752 Å
Density
Contour LevelBy AUTHOR: 0.0298 / Movie #1: 0.027
Minimum - Maximum-0.1001916 - 0.16280524
Average (Standard dev.)0.0002790534 (±0.0042708316)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions272272272
Spacing272272272
CellA=B=C: 204.54399 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.7520.7520.752
M x/y/z272272272
origin x/y/z0.0000.0000.000
length x/y/z204.544204.544204.544
α/β/γ90.00090.00090.000
start NX/NY/NZ535455
NX/NY/NZ134138134
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS272272272
D min/max/mean-0.1000.1630.000

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Supplemental data

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Mask #1

Fileemd_32299_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_32299_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_32299_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : gastric proton pump

EntireName: gastric proton pump
Components
  • Complex: gastric proton pump
    • Protein or peptide: Potassium-transporting ATPase alpha chain 1
    • Protein or peptide: Potassium-transporting ATPase subunit beta
  • Ligand: N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidin-2-amine
  • Ligand: SODIUM IONSodium
  • Ligand: MAGNESIUM ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: water

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Supramolecule #1: gastric proton pump

SupramoleculeName: gastric proton pump / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Sus scrofa (pig)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightExperimental: 135 KDa

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Macromolecule #1: Potassium-transporting ATPase alpha chain 1

MacromoleculeName: Potassium-transporting ATPase alpha chain 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: H+/K+-exchanging ATPase
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 114.456734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGKAENYELY QVELGPGPSG DMAAKMSKKK AGRGGGKRKE KLENMKKEME INDHQLSVAE LEQKYQTSAT KGLSASLAAE LLLRDGPNA LRPPRGTPEY VKFARQLAGG LQCLMWVAAA ICLIAFAIQA SEGDLTTDDN LYLALALIAV VVVTGCFGYY Q EFKSTNII ...String:
MGKAENYELY QVELGPGPSG DMAAKMSKKK AGRGGGKRKE KLENMKKEME INDHQLSVAE LEQKYQTSAT KGLSASLAAE LLLRDGPNA LRPPRGTPEY VKFARQLAGG LQCLMWVAAA ICLIAFAIQA SEGDLTTDDN LYLALALIAV VVVTGCFGYY Q EFKSTNII ASFKNLVPQQ ATVIRDGDKF QINADQLVVG DLVEMKGGDR VPADIRILQA QGCKVDNSSL TGESEPQTRS PE CTHESPL ETRNIAFFST MCLEGTAQGL VVNTGDRTII GRIASLASGV ENEKTPIAIE IEHFVDIIAG LAILFGATFF IVA MCIGYT FLRAMVFFMA IVVAYVPEGL LATVTVCLSL TAKRLASKNC VVKNLEAVET LGSTSVICS(BFD) KTGTLTQNRM TVSHLWFDN HIHSADTTED QSGQTFDQSS ETWRALCRVL TLCNRAAFKS GQDAVPVPKR IVIGDASETA LLKFSELTLG N AMGYRERF PKVCEIPFNS TNKFQLSIHT LEDPRDPRHV LVMKGAPERV LERCSSILIK GQELPLDEQW REAFQTAYLS LG GLGERVL GFCQLYLSEK DYPPGYAFDV EAMNFPTSGL CFAGLVSMID PPRATVPDAV LKCRTAGIRV IMVTGDHPIT AKA IAASVG IISEGSETVE DIAARLRVPV DQVNRKDARA CVINGMQLKD MDPSELVEAL RTHPEMVFAR TSPQQKLVIV ESCQ RLGAI VAVTGDGVND SPALKKADIG VAMGIAGSDA AKNAADMILL DDNFASIVTG VEQGRLIFDN LKKSIAYTLT KNIPE LTPY LIYITVSVPL PLGCITILFI ELCTDIFPSV SLAYEKAESD IMHLRPRNPK RDRLVNEPLA AYSYFQIGAI QSFAGF TDY FTAMAQEGWF PLLCVGLRPQ WENHHLQDLQ DSYGQEWTFG QRLYQQYTCY TVFFISIEMC QIADVLIRKT RRLSAFQ QG FFRNRILVIA IVFQVCIGCF LCYCPGMPNI FNFMPIRFQW WLVPMPFSLL IFVYDEIRKL GVRCCPGSWW DQELYY

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Macromolecule #2: Potassium-transporting ATPase subunit beta

MacromoleculeName: Potassium-transporting ATPase subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 33.113844 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAALQEKKSC SQRMEEFQRY CWNPDTGQML GRTLSRWVWI SLYYVAFYVV MSGIFALCIY VLMRTIDPYT PDYQDQLKSP GVTLRPDVY GEKGLDISYN VSDSTTWAGL AHTLHRFLAG YSPAAQEGSI NCTSEKYFFQ ESFLAPNHTK FSCKFTADML Q NCSGRPDP ...String:
MAALQEKKSC SQRMEEFQRY CWNPDTGQML GRTLSRWVWI SLYYVAFYVV MSGIFALCIY VLMRTIDPYT PDYQDQLKSP GVTLRPDVY GEKGLDISYN VSDSTTWAGL AHTLHRFLAG YSPAAQEGSI NCTSEKYFFQ ESFLAPNHTK FSCKFTADML Q NCSGRPDP TFGFAEGKPC FIIKMNRIVK FLPGNSTAPR VDCAFLDQPR DGPPLQVEYF PANGTYSLHY FPYYGKKAQP HY SNPLVAA KLLNVPRNRD VVIVCKILAE HVSFDNPHDP YEGKVEFKLK IQK

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Macromolecule #3: N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-i...

MacromoleculeName: N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidin-2-amine
type: ligand / ID: 3 / Number of copies: 1 / Formula: 8CK
Molecular weightTheoretical: 362.443 Da
Chemical component information

ChemComp-8CK:
N-(4-fluorophenyl)-4,5-dimethyl-6-[(1R)-1-methyl-3,4-dihydro-1H-isoquinolin-2-yl]pyrimidin-2-amine

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 1
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #7: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 7 / Number of copies: 1 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 12 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 6.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 48.0 e/Å2

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 44404
FSC plot (resolution estimation)

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