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

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Basic information

Entry
Database: PDB / ID: 6eeh
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-J4D / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.629 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 14, 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
Revision 2.0May 1, 2024Group: Data collection / Derived calculations ...Data collection / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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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)30,3275
Polymers28,8441
Non-polymers1,4824
Water1,45981
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.571, 41.795, 72.889
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-J4D / N-[2-hydroxy-3-nitro-5-(nitrosulfonyl)phenyl]-N'-(pentafluorophenyl)urea


Mass: 472.258 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C13H5F5N4O8S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 81 / 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: 43.58 %
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: Aug 4, 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: 29132 / % possible obs: 93 % / Redundancy: 2.7 % / Biso Wilson estimate: 14.1 Å2 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.045 / Rrim(I) all: 0.079 / Χ2: 0.84 / Net I/σ(I): 11.5 / Num. measured all: 77621
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.63-1.662.50.58513870.5820.4510.7431.00888.1
1.66-1.692.60.50413520.6230.3860.6380.83789.2
1.69-1.722.70.44114010.720.3330.5550.8789.9
1.72-1.762.70.36814420.7880.2770.4630.87591.6
1.76-1.792.70.30213900.8390.2270.380.89290.7
1.79-1.842.70.25514270.8730.1910.320.84391.3
1.84-1.882.70.19314330.9120.1450.2430.83792.8
1.88-1.932.70.15914350.9390.120.2010.81691.3
1.93-1.992.70.13414770.9550.10.1680.86794.1
1.99-2.052.70.1114280.9690.0810.1370.85292.5
2.05-2.132.70.09314730.9780.0690.1170.88993.6
2.13-2.212.70.0814920.9830.0580.10.79794.6
2.21-2.312.70.07214600.9850.0520.0890.83594.8
2.31-2.432.70.06614870.9870.0470.0810.83495.6
2.43-2.592.70.06215090.990.0430.0760.84695.9
2.59-2.792.70.05115170.990.0350.0620.77296
2.79-3.072.70.04615010.9930.030.0550.78496.3
3.07-3.512.70.04215530.9920.0280.0510.7997.4
3.51-4.422.70.03915000.9940.0250.0470.77294.6
4.42-502.80.0414680.9930.0260.0480.8289.2

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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: 1.629→29.371 Å / SU ML: 0.16 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 18.64 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1871 1427 4.93 %
Rwork0.1595 27511 -
obs0.1609 28938 92.25 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 95.29 Å2 / Biso mean: 20.7556 Å2 / Biso min: 4.79 Å2
Refinement stepCycle: final / Resolution: 1.629→29.371 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2042 0 88 81 2211
Biso mean--43.89 27.82 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072192
X-RAY DIFFRACTIONf_angle_d1.2342993
X-RAY DIFFRACTIONf_chiral_restr0.066300
X-RAY DIFFRACTIONf_plane_restr0.01383
X-RAY DIFFRACTIONf_dihedral_angle_d11.6731711
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 (%)
1.6289-1.68710.31281340.28622480261484
1.6871-1.75460.21061360.20312645278189
1.7546-1.83440.21871390.18112659279890
1.8344-1.93110.23081400.16342729286992
1.9311-2.05210.18371490.14422755290493
2.0521-2.21050.17461350.1492827296294
2.2105-2.43290.16131480.15742804295295
2.4329-2.78470.19761510.17232883303496
2.7847-3.50750.20821510.16332904305597
3.5075-29.37570.14791440.13132825296992
Refinement TLS params.Method: refined / Origin x: -9.1124 Å / Origin y: -1.1946 Å / Origin z: 16.0265 Å
111213212223313233
T0.0538 Å2-0.002 Å2-0 Å2-0.0494 Å20.0045 Å2--0.0554 Å2
L0.87 °2-0.0708 °2-0.0417 °2-0.6381 °2-0.0555 °2--0.7696 °2
S-0.0048 Å °0.0001 Å °0.0529 Å °-0.0207 Å °0.0043 Å °-0.022 Å °-0.0013 Å °0.0086 Å °-0 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 261
2X-RAY DIFFRACTION1allB262
3X-RAY DIFFRACTION1allC2 - 36
4X-RAY DIFFRACTION1allC39 - 89
5X-RAY DIFFRACTION1allC99 - 100
6X-RAY DIFFRACTION1allC105 - 144
7X-RAY DIFFRACTION1allC146 - 161
8X-RAY DIFFRACTION1allD2 - 4

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