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

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Basic information

Entry
Database: PDB / ID: 6ebe
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 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 activity / cyanamide hydratase / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / morphogenesis of an epithelium ...positive regulation of cellular pH reduction / positive regulation of dipeptide transmembrane transport / regulation of monoatomic anion transport / secretion / cyanamide hydratase activity / cyanamide hydratase / arylesterase activity / regulation of chloride transport / Reversible hydration of carbon dioxide / morphogenesis of an epithelium / angiotensin-activated signaling pathway / regulation of intracellular pH / positive regulation of synaptic transmission, GABAergic / 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 / apical part of cell / myelin sheath / extracellular exosome / zinc ion binding / plasma membrane / cytoplasm / cytosol
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-J3V / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.88 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 6, 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)29,4183
Polymers28,9331
Non-polymers4862
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.861, 41.811, 72.909
Angle α, β, γ (deg.)90.000, 104.560, 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: 28932.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / 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-J3V / 4-hydroxy-3-nitro-5-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)benzene-1-sulfonamide


Mass: 420.321 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H11F3N4O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 43.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.8 / Details: 1.6 M Sodium citrate, 50 mM Tris-HCl, pH 7.8

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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 28, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.88→50 Å / Num. obs: 18329 / % possible obs: 88.9 % / Redundancy: 2.4 % / Biso Wilson estimate: 20.74 Å2 / Rmerge(I) obs: 0.095 / Rpim(I) all: 0.069 / Rrim(I) all: 0.118 / Χ2: 0.904 / Net I/σ(I): 6.2 / Num. measured all: 44675
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.88-1.912.30.5929160.6250.4470.7470.8990.8
1.91-1.952.30.569330.6480.4290.710.87189.5
1.95-1.982.30.4259280.7260.3190.5350.84891.9
1.98-2.032.40.3859140.7780.2910.4860.89290.8
2.03-2.072.30.369530.7880.2750.4560.92291.6
2.07-2.122.40.3029070.8590.2240.3790.95990.7
2.12-2.172.40.2429430.9010.1790.3030.90691.1
2.17-2.232.40.2249110.9110.1660.2810.94790
2.23-2.292.40.1989370.9310.1460.2470.90991.1
2.29-2.372.40.1829250.930.1350.2280.93490.1
2.37-2.452.40.179320.9450.1240.2120.99690.4
2.45-2.552.40.1619320.9570.1180.2011.00490.7
2.55-2.672.40.1379210.9690.0990.170.94189.7
2.67-2.812.50.1139250.9750.0820.140.94589.7
2.81-2.982.50.0959140.9840.0680.1170.97488.1
2.98-3.212.50.0729060.9880.0510.0890.9188.1
3.21-3.542.60.0549050.9940.0380.0660.88386.8
3.54-4.052.60.0418830.9960.0280.050.88585.7
4.05-5.12.60.038840.9980.0210.0370.80783.7
5.1-502.70.0288600.9970.0190.0340.68178.7

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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: 1.88→32.383 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 21.6
RfactorNum. reflection% reflection
Rfree0.2277 900 4.95 %
Rwork0.1682 --
obs0.171 18182 88.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 90.56 Å2 / Biso mean: 23.9742 Å2 / Biso min: 7.66 Å2
Refinement stepCycle: final / Resolution: 1.88→32.383 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 29 41 2119
Biso mean--46.33 25.7 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092139
X-RAY DIFFRACTIONf_angle_d1.2952908
X-RAY DIFFRACTIONf_chiral_restr0.08299
X-RAY DIFFRACTIONf_plane_restr0.012376
X-RAY DIFFRACTIONf_dihedral_angle_d14.4751714
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 6

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8795-1.99720.29481530.22222784293786
1.9972-2.15140.26951500.19282931308191
2.1514-2.36790.23921550.17962944309991
2.3679-2.71030.24721490.18852944309390
2.7103-3.41420.22081490.17292888303788
3.4142-32.38830.19111440.13352791293583
Refinement TLS params.Method: refined / Origin x: -9.7954 Å / Origin y: -1.75 Å / Origin z: 16.1507 Å
111213212223313233
T0.0921 Å20.0034 Å2-0.0008 Å2-0.0941 Å20.0024 Å2--0.095 Å2
L0.6411 °2-0.0417 °20.0134 °2-0.5989 °2-0.0686 °2--0.4964 °2
S-0.0023 Å °-0.0107 Å °0.023 Å °-0.0113 Å °-0.001 Å °-0.0135 Å °0.035 Å °-0.013 Å °-0.0002 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 261
2X-RAY DIFFRACTION1allB262
3X-RAY DIFFRACTION1allC1 - 40
4X-RAY DIFFRACTION1allC44 - 50
5X-RAY DIFFRACTION1allD1

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