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- PDB-6zja: Helicobacter pylori urease with inhibitor bound in the active site -

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Basic information

Entry
Database: PDB / ID: 6zja
TitleHelicobacter pylori urease with inhibitor bound in the active site
Components
  • Urease subunit alpha
  • Urease subunit beta
KeywordsHYDROLASE / dodecamer / bi nickel center / enzyme / cytoplasm
Function / homology
Function and homology information


urease complex / urease / urease activity / urea catabolic process / nickel cation binding / cytoplasm
Similarity search - Function
Urease, gamma-beta subunit / Urease active site / Urease active site. / Urease nickel binding site / Urease nickel ligands signature. / Urease, beta subunit / Urease, alpha subunit / Urease alpha subunit, C-terminal / Urease, beta subunit superfamily / Urease beta subunit ...Urease, gamma-beta subunit / Urease active site / Urease active site. / Urease nickel binding site / Urease nickel ligands signature. / Urease, beta subunit / Urease, alpha subunit / Urease alpha subunit, C-terminal / Urease, beta subunit superfamily / Urease beta subunit / Urease domain profile. / Urease alpha-subunit, N-terminal domain / Urease alpha-subunit, N-terminal domain / Urease, gamma/gamma-beta subunit / Urease, gamma subunit superfamily / Urease, gamma subunit / Amidohydrolase family / Metal-dependent hydrolase, composite domain superfamily / Amidohydrolase-related / Metal-dependent hydrolase
Similarity search - Domain/homology
Chem-DJM / NICKEL (II) ION / Urease subunit beta / Urease subunit alpha / Urease subunit alpha / Urease subunit beta
Similarity search - Component
Biological speciesHelicobacter pylori (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2 Å
AuthorsLuecke, H. / Cunha, E.
Funding support Norway, United States, 2items
OrganizationGrant numberCountry
Research Council of Norway275207 Norway
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI78000 United States
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structure of Helicobacter pylori urease with an inhibitor in the active site at 2.0 Å resolution.
Authors: Eva S Cunha / Xiaorui Chen / Marta Sanz-Gaitero / Deryck J Mills / Hartmut Luecke /
Abstract: Infection of the human stomach by Helicobacter pylori remains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of ...Infection of the human stomach by Helicobacter pylori remains a worldwide problem and greatly contributes to peptic ulcer disease and gastric cancer. Without active intervention approximately 50% of the world population will continue to be infected with this gastric pathogen. Current eradication, called triple therapy, entails a proton-pump inhibitor and two broadband antibiotics, however resistance to either clarithromycin or metronidazole is greater than 25% and rising. Therefore, there is an urgent need for a targeted, high-specificity eradication drug. Gastric infection by H. pylori depends on the expression of a nickel-dependent urease in the cytoplasm of the bacteria. Here, we report the 2.0 Å resolution structure of the 1.1 MDa urease in complex with an inhibitor by cryo-electron microscopy and compare it to a β-mercaptoethanol-inhibited structure at 2.5 Å resolution. The structural information is of sufficient detail to aid in the development of inhibitors with high specificity and affinity.
History
DepositionJun 28, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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

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Structure visualization

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  • Deposited structure unit
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Structure viewerMolecule:
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Assembly

Deposited unit
A: Urease subunit alpha
B: Urease subunit beta
C: Urease subunit alpha
E: Urease subunit alpha
G: Urease subunit alpha
I: Urease subunit alpha
K: Urease subunit alpha
M: Urease subunit alpha
O: Urease subunit alpha
Q: Urease subunit alpha
S: Urease subunit alpha
U: Urease subunit alpha
W: Urease subunit alpha
J: Urease subunit beta
D: Urease subunit beta
F: Urease subunit beta
H: Urease subunit beta
L: Urease subunit beta
N: Urease subunit beta
P: Urease subunit beta
R: Urease subunit beta
T: Urease subunit beta
V: Urease subunit beta
X: Urease subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,066,47660
Polymers1,061,73924
Non-polymers4,73736
Water57,4863191
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area203100 Å2
ΔGint-1004 kcal/mol
Surface area269030 Å2
MethodPISA

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Components

#1: Protein
Urease subunit alpha / Urea amidohydrolase subunit alpha


Mass: 26645.703 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria) / Gene: ureA, BGL58_00110, D2C78_00705, DD749_00755 / Production host: Escherichia coli (E. coli)
References: UniProt: A0A293SGE9, UniProt: P14916*PLUS, urease
#2: Protein
Urease subunit beta / Urea amidohydrolase subunit beta


Mass: 61832.531 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria)
Gene: ureC, ureB, ACM26_03100, ACM31_01665, AEY53_07315, AEY54_04500, BB390_03210, BB400_00890, BB458_02040, BB472_00115, BB483_06885, BCM300_00080, BGL59_06905, BGL62_00955, BGL74_08355, BGL78_ ...Gene: ureC, ureB, ACM26_03100, ACM31_01665, AEY53_07315, AEY54_04500, BB390_03210, BB400_00890, BB458_02040, BB472_00115, BB483_06885, BCM300_00080, BGL59_06905, BGL62_00955, BGL74_08355, BGL78_03465, BGL80_00980, BZK19_03120, BZK22_02015, BZK28_01040, C2R48_07340, C2R49_05480, C2R51_07515, C2R54_00600, C2R57_07640, C2R76_03750, C2R81_00275, C2R85_01915, C2R92_02560, CV727_07335, CV730_01155, D2C74_07740, D2C77_03985, D2C79_06860, DD741_00890, DD749_00750, DD779_00665, DD783_00075, DDP32_00750, DDP35_00500, EC528_04020, EC532_02160, EC572_01665, EC592_02340, EC594_04345, EC598_01685, ECB88_00905, ECB90_01230, ECC11_01355, ECC14_06065, ECC20_02355, ECC23_04175, ECC26_01225, ECC27_04455, ECC29_00335, ECC38_01340, ECC45_00115, ECE48_05900, EDB75_03310, EPC84_05055, HPY1198_04550, NCTC13207_01207, NCTC13338_01433, NCTC13345_00234
Production host: Escherichia coli (E. coli)
References: UniProt: A0A086RWB6, UniProt: P69996*PLUS, urease
#3: Chemical...
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: Ni
#4: Chemical
ChemComp-DJM / 2-{[1-(3,5-dimethylphenyl)-1H-imidazol-2-yl]sulfanyl}-N-hydroxyacetamide


Mass: 277.342 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C13H15N3O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3191 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 1.1 MDa Helicobacter pylori Urease / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 1.1 MDa / Experimental value: NO
Source (natural)Organism: Helicobacter pylori (bacteria) / Strain: UMAB41 / Cellular location: Cytoplasm
Source (recombinant)Organism: Escherichia coli (E. coli) / Plasmid: pHP808, pHP902
Buffer solutionpH: 8
Buffer component
IDConc.NameBuffer-ID
120 mMHepes1
21 mMEDTA1
31 mMBME1
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 70 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 956 / Details: Used 718 movies

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Processing

SoftwareName: PHENIX / Version: 1.18.1_3865: / Classification: refinement
EM software
IDNameVersionCategory
4RELION3.0 betaCTF correction
7Coot0.8.9model fitting
9RELION3.0 betainitial Euler assignment
10RELION3.0 betafinal Euler assignment
11RELION3.0 betaclassification
12RELION3.0 beta3D reconstruction
13PHENIX1.18model refinement
CTF correctionDetails: Relion 3.0 beta per image and per particle / Type: NONE
Particle selectionNum. of particles selected: 203000
SymmetryPoint symmetry: T (tetrahedral)
3D reconstructionResolution: 2 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 187461 / Details: Relion was used for resconstruction / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
11E9Z

1e9z

A1
21E9Z

1e9z

B1
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00576092
ELECTRON MICROSCOPYf_angle_d0.854102648
ELECTRON MICROSCOPYf_dihedral_angle_d18.08928296
ELECTRON MICROSCOPYf_chiral_restr0.05711400
ELECTRON MICROSCOPYf_plane_restr0.00613440

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