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- PDB-7w47: Crystal structure of the gastric proton pump complexed with tegoprazan -

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Basic information

Entry
Database: PDB / ID: 7w47
TitleCrystal structure of the gastric proton pump complexed with tegoprazan
Components(Potassium-transporting ATPase ...) x 2
KeywordsHYDROLASE / 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
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 ...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
Tegoprazan / RUBIDIUM ION / Potassium-transporting ATPase subunit beta / Potassium-transporting ATPase alpha chain 1
Similarity search - Component
Biological speciesSus scrofa (pig)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsAbe, K. / Tanaka, S. / Morita, M. / Yamagishi, T.
Funding support Japan, 1items
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, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 5, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Potassium-transporting ATPase alpha chain 1
B: Potassium-transporting ATPase subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,90210
Polymers147,5712
Non-polymers1,3328
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5260 Å2
ΔGint-39 kcal/mol
Surface area53470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.990, 104.990, 367.790
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Space group name HallP312"
Symmetry operation#1: x,y,z
#2: -y,x-y,z+1/3
#3: -x+y,-x,z+2/3
#4: x-y,-y,-z+2/3
#5: -x,-x+y,-z+1/3
#6: y,x,-z

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Components

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Potassium-transporting ATPase ... , 2 types, 2 molecules AB

#1: Protein Potassium-transporting ATPase alpha chain 1 / Gastric H(+)/K(+) ATPase subunit alpha / Proton pump


Mass: 114456.734 Da / Num. of mol.: 1 / Mutation: R221C, S591C, G1006S
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
#2: Protein Potassium-transporting ATPase subunit beta / Gastric H(+)/K(+) ATPase subunit beta / Proton pump beta chain / gp60-90


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

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Sugars , 1 types, 3 molecules

#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 4 types, 88 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-RB / RUBIDIUM ION


Mass: 85.468 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Rb / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-8BN / Tegoprazan


Mass: 387.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19F2N3O3 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 4.22 Å3/Da / Density % sol: 70.83 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 10% glycerol, 0.2 M RbCl, 20% PEG2000MME, 3% tert-BuOH, 5 mM beta-MeSH

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Data collection

DiffractionMean temperature: 77 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 25, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→48.26 Å / Num. obs: 48211 / % possible obs: 84.77 % / Redundancy: 2 % / Biso Wilson estimate: 66.81 Å2 / CC1/2: 0.998 / Net I/σ(I): 12.41
Reflection shellResolution: 3.001→3.108 Å / Num. unique obs: 1079 / CC1/2: 0.276 / % possible all: 22.92

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ylv

5ylv


Resolution: 3→48.26 Å / SU ML: 0.4779 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 31.5534
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2853 2013 4.92 %
Rwork0.2221 38881 -
obs0.2252 40894 84.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.58 Å2
Refinement stepCycle: LAST / Resolution: 3→48.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9747 0 74 83 9904
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.010310045
X-RAY DIFFRACTIONf_angle_d1.323213658
X-RAY DIFFRACTIONf_chiral_restr0.08391550
X-RAY DIFFRACTIONf_plane_restr0.00811757
X-RAY DIFFRACTIONf_dihedral_angle_d12.82641384
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.080.6441390.4603649X-RAY DIFFRACTION20.47
3.08-3.160.3881500.37971050X-RAY DIFFRACTION32.39
3.16-3.250.4514730.32961574X-RAY DIFFRACTION48.83
3.25-3.360.35471460.29742651X-RAY DIFFRACTION82.46
3.36-3.480.32881670.26963212X-RAY DIFFRACTION99.94
3.48-3.620.3661640.25643261X-RAY DIFFRACTION99.97
3.62-3.780.30421410.22913260X-RAY DIFFRACTION100
3.78-3.980.27841880.21763215X-RAY DIFFRACTION99.91
3.98-4.230.25871850.19813246X-RAY DIFFRACTION99.94
4.23-4.550.2621910.17353288X-RAY DIFFRACTION99.94
4.56-5.010.24651630.16473264X-RAY DIFFRACTION100
5.01-5.740.27831580.19933314X-RAY DIFFRACTION99.91
5.74-7.220.28261660.23423358X-RAY DIFFRACTION100
7.22-48.260.24641820.22433539X-RAY DIFFRACTION99.84
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0178750191188-0.000506945767441-0.0171325466114-8.92394975933E-50.003703105012370.0127931924147-0.01948446524910.005262294222260.0155699670338-0.009584102670070.119320941777-0.133808157880.0145691143899-0.0232467845248-0.0001959615250140.3380356135270.06828830525360.06302841392360.471700542637-0.1737471641710.53929886299867.0109735953-14.5184584225-17.913105809
20.05343498471180.0265640058351-0.007960507782690.035968487608-0.01412440223260.0222495952087-0.009137729517540.02317078516540.01480841401410.0314013466578-0.01071289878510.00150955664172-0.01864693095070.0083707586037-0.0212794754250.0733793573549-0.1402735706170.02879190855130.245234289815-0.04783471028870.22292000324546.8068990277-29.3599629528-56.2403240486
30.0428698464101-0.0114619929663-0.0094924921160.01607321529830.002559638614410.0116835474958-0.0598444951967-0.00695722080862-0.00867123701395-0.0116388897428-0.05588051726410.04000906612690.0082910225365-0.01367916942265.27338971224E-50.233282834561-0.003891803981440.05469193197470.25431128938-0.1008003439360.34496944920958.363457552-15.8041608597-8.03901504456
40.02496984021450.0922591961331-0.0481700083150.0750861076793-0.02798858820080.0687281501290.05497730628340.1080558459180.07872079226440.09811437658540.05870374111570.129204531286-0.115735414995-0.03732797280960.03245143004680.1677798430780.003087692265870.2189245201730.211086444214-0.1798953905560.20588207907635.8310767149-22.6628849771-5.69776713176
50.1072941806170.0771510988122-0.00487250518985-0.003160922802190.00975864499780.0130745726207-0.01965756874620.119439850153-0.1218639559990.01015975542090.01481951096090.01007846228110.0597323499865-0.1026473950150.0648149608233-0.0268016473443-0.2585634036210.04956806713820.288425419218-0.1740454030950.19037754047137.0870888016-41.1660318105-39.9777759596
60.02863745437610.0215613871079-0.007980488439510.0156699173504-0.005991005691080.00132320306567-0.0686231427611-0.00151182862214-0.1026267593870.00713229832433-0.02725308583560.0497558076640.0549496210088-0.0309950395541-0.04969853951560.241544136894-0.2036724238230.1848803452990.50427007473-0.130337505070.21463379581721.1552476239-41.6121802176-54.4099060696
7-2.96904215665E-5-0.0026272495280.00273331080694-0.00219206533235-0.002658373895920.00170973844775-0.04210222813160.00419517930985-0.0085669394930.0197545465748-0.01205633103810.01996288349890.0248530191310.01343229894732.90676963095E-50.512021188379-0.2869329129610.157236792220.499545515-0.1242351520110.40538444605527.2724140195-61.0138987106-59.7756246487
80.0203342110208-0.0268827074050.006044658698010.0505868105362-0.01003872906510.00333149444773-0.03343618578090.0008280442272190.01830268686860.0287479905608-0.107151563807-0.01019580362210.0190654778907-0.112999096486-0.02910326883260.178503717921-0.126267255922-0.06326044228210.593708948589-0.1341990752920.29948063129632.8463282338-41.0100690496-101.2571921
90.0126400944770.00912956701260.01610892350250.0003219966455540.006279272097950.0176366414163-0.01216907421350.04218495461770.0479016342605-0.0105744519557-0.06576006257650.02408443031330.00436755667621-0.02066677999794.37249008825E-50.300990834331-0.0948128070883-0.0131172749570.716351194309-0.1352709201930.30091982024628.1064327024-41.0667188783-107.318258234
10-0.0002750569658040.000109439626319-0.00013436144637-0.0003067451467560.000215862118333-0.0003193299564260.00852230998687-0.00156232574478-0.003481470837880.007655602745710.005578183518480.008671336268840.00407989130623-0.007105763089539.93777676654E-60.6156767668820.0535791003735-0.006728852115350.652743680729-0.008031489765250.70941463623939.4481746028-18.5389168296-107.116517884
110.159191542769-0.0290629712326-0.02581376415990.0146742264129-0.004860337550630.01172322227860.00196108278296-0.06272589232270.1335920945050.0200429986456-0.0627274038054-0.02634975395140.00311611604973-0.1385654621-0.008127497204840.383254112731-0.0695983884472-0.008998339555450.717926039472-0.1244733419870.23762189626432.8053739449-31.9961752022-103.151645205
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 47 through 107 )
2X-RAY DIFFRACTION2chain 'A' and (resid 108 through 168 )
3X-RAY DIFFRACTION3chain 'A' and (resid 169 through 291 )
4X-RAY DIFFRACTION4chain 'A' and (resid 292 through 617 )
5X-RAY DIFFRACTION5chain 'A' and (resid 618 through 946 )
6X-RAY DIFFRACTION6chain 'A' and (resid 947 through 1033 )
7X-RAY DIFFRACTION7chain 'B' and (resid 31 through 64 )
8X-RAY DIFFRACTION8chain 'B' and (resid 65 through 139 )
9X-RAY DIFFRACTION9chain 'B' and (resid 140 through 197 )
10X-RAY DIFFRACTION10chain 'B' and (resid 198 through 214 )
11X-RAY DIFFRACTION11chain 'B' and (resid 215 through 290 )

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