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- PDB-6eeo: Bioreductive 4-hydroxy-3-nitro-5-ureido-benzenesulfonamides selec... -

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Basic information

Entry
Database: PDB / ID: 6eeo
TitleBioreductive 4-hydroxy-3-nitro-5-ureido-benzenesulfonamides selectively target the tumor-associated carbonic anhydrase isoforms IX and XII and show hypoxia-enhanced cytotoxicity against human cancer cell lines.
ComponentsCarbonic anhydrase 2
KeywordsLYASE/LYASE inhibitor / Hypoxia / carbonic anhydrase IX / carbonic anhydrase XII / inhibition / anti-proliferative. / LYASE / LYASE-LYASE inhibitor complex
Function / homology
Function and homology information


positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase / cyanamide hydratase activity / regulation of chloride transport / arylesterase activity / Reversible hydration of carbon dioxide / positive regulation of synaptic transmission, GABAergic ...positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase / cyanamide hydratase activity / regulation of chloride transport / arylesterase activity / Reversible hydration of carbon dioxide / positive regulation of synaptic transmission, GABAergic / angiotensin-activated signaling pathway / morphogenesis of an epithelium / regulation of intracellular pH / carbonic anhydrase / carbonate dehydratase activity / carbon dioxide transport / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / neuron cellular homeostasis / one-carbon metabolic process / apical part of cell / myelin sheath / extracellular exosome / zinc ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Carbonic Anhydrase II / Alpha carbonic anhydrase / Carbonic anhydrase, alpha-class, conserved site / Alpha-carbonic anhydrases signature. / Carbonic anhydrase, alpha-class / Alpha carbonic anhydrase domain / Alpha carbonic anhydrase domain superfamily / Eukaryotic-type carbonic anhydrase / Alpha-carbonic anhydrases profile. / Eukaryotic-type carbonic anhydrase ...Carbonic Anhydrase II / Alpha carbonic anhydrase / Carbonic anhydrase, alpha-class, conserved site / Alpha-carbonic anhydrases signature. / Carbonic anhydrase, alpha-class / Alpha carbonic anhydrase domain / Alpha carbonic anhydrase domain superfamily / Eukaryotic-type carbonic anhydrase / Alpha-carbonic anhydrases profile. / Eukaryotic-type carbonic anhydrase / Roll / Alpha Beta
Similarity search - Domain/homology
Chem-J6V / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.719 Å
AuthorsSingh, S. / McKenna, R. / Supuran, C.T. / Nocentini, A. / Lomelino, C. / Lucarini, E. / Bartolucci, G. / Mannelli, L.D.C. / Ghelardini, C. / Gratteri, P.
CitationJournal: J. Med. Chem. / Year: 2018
Title: 4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative Profiles.
Authors: Nocentini, A. / Trallori, E. / Singh, S. / Lomelino, C.L. / Bartolucci, G. / Di Cesare Mannelli, L. / Ghelardini, C. / McKenna, R. / Gratteri, P. / Supuran, C.T.
History
DepositionAug 15, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Carbonic anhydrase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,2943
Polymers28,8441
Non-polymers4502
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.590, 41.940, 72.756
Angle α, β, γ (deg.)90.000, 104.080, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Carbonic anhydrase 2 / Carbonate dehydratase II / Carbonic anhydrase C / CAC / Carbonic anhydrase II / CA-II


Mass: 28844.465 Da / Num. of mol.: 1 / Mutation: A65S, N67Q, E69T, I91L, F131V, K170E, L204A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CA2 / Production host: Escherichia coli (E. coli) / References: UniProt: P00918, carbonic anhydrase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-J6V / 3-{[(4-fluoro-3-methylphenyl)carbamoyl]amino}-4-hydroxy-5-nitrobenzene-1-sulfonamide


Mass: 384.340 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13FN4O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O

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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: 2.19 Å3/Da / Density % sol: 43.71 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.8 / Details: 1.6 M Sodium citrate, 50 mM Tris-HCl

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jul 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.72→20 Å / Num. obs: 26523 / % possible obs: 99.2 % / Redundancy: 3.8 % / Biso Wilson estimate: 19.11 Å2 / Rmerge(I) obs: 0.061 / Rpim(I) all: 0.035 / Rrim(I) all: 0.07 / Χ2: 0.926 / Net I/σ(I): 13.6 / Num. measured all: 100622
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.72-1.752.60.40111570.7590.3020.5060.74686.2
1.75-1.783.10.37512760.8280.2510.4550.79697.4
1.78-1.823.70.32813360.8920.1950.3830.844100
1.82-1.853.80.26113120.9110.1540.3040.84699.9
1.85-1.893.80.22413080.9380.1340.2620.902100
1.89-1.943.80.18913610.9580.1110.220.915100
1.94-1.993.80.15313080.9660.0910.1780.919100
1.99-2.043.90.13913400.9730.0810.1611.003100
2.04-2.13.80.11713110.980.0690.1371.008100
2.1-2.173.90.113280.9870.0580.1161.022100
2.17-2.243.90.09313490.9850.0550.1091.032100
2.24-2.333.90.08113270.9910.0470.0940.986100
2.33-2.443.90.07413280.9920.0430.0850.946100
2.44-2.573.90.06813310.9920.0390.0790.957100
2.57-2.7340.05913510.9950.0340.0680.865100
2.73-2.9440.05513340.9950.0320.0640.932100
2.94-3.2340.04813570.9950.0280.0550.852100
3.23-3.740.04613400.9950.0260.0530.888100
3.7-4.6540.04613750.9910.0270.0530.921100
4.65-203.90.04913940.9940.0290.0571.003100

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Processing

Software
NameVersionClassification
PHENIX1.10pre_2097refinement
HKL-2000data scaling
PDB_EXTRACT3.24data extraction
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3KS3

3ks3


Resolution: 1.719→18.968 Å / SU ML: 0.17 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2069 1331 5.03 %
Rwork0.1729 25151 -
obs0.1745 26482 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 82.4 Å2 / Biso mean: 24.4039 Å2 / Biso min: 8.9 Å2
Refinement stepCycle: final / Resolution: 1.719→18.968 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2042 0 27 24 2093
Biso mean--46.44 31.02 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092171
X-RAY DIFFRACTIONf_angle_d1.5962961
X-RAY DIFFRACTIONf_chiral_restr0.07306
X-RAY DIFFRACTIONf_plane_restr0.013388
X-RAY DIFFRACTIONf_dihedral_angle_d10.82198
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.7191-1.78050.26681270.23012251237890
1.7805-1.85180.22211280.183225332661100
1.8518-1.9360.23461350.182125202655100
1.936-2.03790.19891260.160925292655100
2.0379-2.16540.19221270.167925222649100
2.1654-2.33240.22261410.183225282669100
2.3324-2.56660.22631300.195825352665100
2.5666-2.93680.21731420.204525452687100
2.9368-3.69550.22831320.1825602692100
3.6955-18.96920.16591430.134926282771100
Refinement TLS params.Method: refined / Origin x: -9.4498 Å / Origin y: -1.6901 Å / Origin z: 16.1694 Å
111213212223313233
T0.1018 Å2-0.0012 Å2-0.0017 Å2-0.0998 Å20.0056 Å2--0.108 Å2
L0.9474 °2-0.035 °20.0357 °2-0.6612 °2-0.0689 °2--0.8644 °2
S-0.0197 Å °-0.0044 Å °0.0374 Å °-0.0277 Å °0.0092 Å °-0.0123 Å °0.0113 Å °-0.0049 Å °-0.0001 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 261
2X-RAY DIFFRACTION1allB262
3X-RAY DIFFRACTION1allC3 - 44
4X-RAY DIFFRACTION1allD1

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