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

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Basic information

Entry
Database: PDB / ID: 6eea
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 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 / positive regulation of synaptic transmission, GABAergic / 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 / 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: 1.63 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 13, 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)29,7514
Polymers28,8441
Non-polymers9063
Water70339
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.586, 41.884, 72.785
Angle α, β, γ (deg.)90.000, 104.130, 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-J3V / 4-hydroxy-3-nitro-5-({[4-(trifluoromethyl)phenyl]carbamoyl}amino)benzene-1-sulfonamide


Mass: 420.321 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H11F3N4O6S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 39 / 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: 2.18 Å3/Da / Density % sol: 43.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.8 / Details: 1.6 M Sosium 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: Aug 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.63→50 Å / Num. obs: 29170 / % possible obs: 93.1 % / Redundancy: 3 % / Biso Wilson estimate: 13.36 Å2 / Rmerge(I) obs: 0.063 / Rpim(I) all: 0.043 / Rrim(I) all: 0.077 / Χ2: 0.898 / Net I/σ(I): 13.5 / Num. measured all: 86631
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.63-1.662.90.46613700.7250.3270.571.14588
1.66-1.6930.39113880.790.2730.4780.96389.1
1.69-1.7230.33913730.8290.2370.4140.91489.1
1.72-1.7630.28314280.8750.1950.3440.88991.1
1.76-1.7930.23613720.9080.1630.2870.88989.7
1.79-1.8430.20114030.9220.140.2460.83190.6
1.84-1.8830.15514320.9480.1070.1890.81892.1
1.88-1.9330.13214270.9670.0920.1610.83190.6
1.93-1.9930.1114570.9760.0750.1340.86493.3
1.99-2.0530.09514270.9780.0660.1160.87692.2
2.05-2.1330.08214510.9850.0570.10.86692.8
2.13-2.2130.07514970.9880.0520.0910.87294.3
2.21-2.3130.0714520.9870.0480.0850.89794.1
2.31-2.4330.06414640.9880.0450.0790.92394.7
2.43-2.5930.0615070.9920.0410.0720.87995.6
2.59-2.7930.05515120.9910.0380.0670.88795.7
2.79-3.0730.05114930.9930.0350.0610.87995.7
3.07-3.5130.04415540.9940.030.0530.89597.6
3.51-4.422.90.04315500.9930.0290.0520.89597.9
4.42-502.90.04716130.9910.0310.0560.97397.9

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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: 1.63→29.407 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 19.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1973 1451 4.98 %
Rwork0.1721 27670 -
obs0.1734 29121 92.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.76 Å2 / Biso mean: 19.4199 Å2 / Biso min: 4.38 Å2
Refinement stepCycle: final / Resolution: 1.63→29.407 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2042 0 57 39 2138
Biso mean--57.04 29.57 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072160
X-RAY DIFFRACTIONf_angle_d1.4582943
X-RAY DIFFRACTIONf_chiral_restr0.065300
X-RAY DIFFRACTIONf_plane_restr0.01379
X-RAY DIFFRACTIONf_dihedral_angle_d12.2491710
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 (%)
1.6301-1.68840.23021340.23412591272587
1.6884-1.75590.22721440.18252643278790
1.7559-1.83580.18461350.17542643277890
1.8358-1.93260.22141420.16852723286591
1.9326-2.05370.1841420.15692739288193
2.0537-2.21220.18041490.17232797294694
2.2122-2.43470.21731410.18052780292194
2.4347-2.78680.23011550.19632859301496
2.7868-3.51010.21871480.18322898304697
3.5101-29.41180.15981610.14432997315898
Refinement TLS params.Method: refined / Origin x: -9.2657 Å / Origin y: -1.4107 Å / Origin z: 15.9279 Å
111213212223313233
T0.0465 Å2-0.0038 Å2-0.0022 Å2-0.045 Å20.0019 Å2--0.0511 Å2
L0.6723 °2-0.0622 °2-0.115 °2-0.4567 °2-0.071 °2--0.6243 °2
S-0.0019 Å °-0.0109 Å °0.0398 Å °-0.03 Å °0.0072 Å °-0.0269 Å °0.0041 Å °-0.0005 Å °-0.0003 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 261
2X-RAY DIFFRACTION1allB1 - 18
3X-RAY DIFFRACTION1allB52 - 98
4X-RAY DIFFRACTION1allB103 - 143
5X-RAY DIFFRACTION1allC262
6X-RAY DIFFRACTION1allD2 - 3

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