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

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Basic information

Entry
Database: PDB / ID: 6ecz
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/LYAS INHIBITOR / Hypoxia / carbonic anhydrase IX / carbonic anhydrase XII / inhibition / anti-proliferative. / LYASE / LYASE-LYAS 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 / 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 / cyanamide hydratase activity / 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 / 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-J4D / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.21 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 8, 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)29,4703
Polymers28,9331
Non-polymers5382
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.880, 41.884, 72.905
Angle α, β, γ (deg.)90.000, 104.450, 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-J4D / N-[2-hydroxy-3-nitro-5-(nitrosulfonyl)phenyl]-N'-(pentafluorophenyl)urea


Mass: 472.258 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H5F5N4O8S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / 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: 43.87 %
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 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.21→50 Å / Num. obs: 12387 / % possible obs: 96.8 % / Redundancy: 3.8 % / Biso Wilson estimate: 31.82 Å2 / Rmerge(I) obs: 0.143 / Rpim(I) all: 0.085 / Rrim(I) all: 0.167 / Χ2: 0.908 / Net I/σ(I): 5.4 / Num. measured all: 46631
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.21-2.253.80.6735640.7250.3990.7830.85693.7
2.25-2.293.80.5636210.7640.3340.6550.85996.1
2.29-2.333.80.5466110.790.3220.6340.88694.7
2.33-2.383.80.5045950.7810.2980.5860.89794
2.38-2.433.80.4426010.7920.2610.5130.89697.7
2.43-2.493.80.4326040.8430.2540.5010.89594.4
2.49-2.553.80.3696100.8790.2190.430.91895.8
2.55-2.623.80.3886280.8680.230.4510.96397.7
2.62-2.73.80.3126010.8970.1840.3630.95694.1
2.7-2.783.80.2656140.9230.1580.3080.89199.2
2.78-2.883.80.2446160.9360.1440.2840.96794.5
2.88-33.80.2056450.9580.1210.2390.92298.9
3-3.143.80.185960.9630.1070.209196.1
3.14-3.33.80.1386370.9760.0830.1610.95797
3.3-3.513.80.116250.9870.0650.1280.9899.4
3.51-3.783.80.0916270.990.0540.1060.9597.8
3.78-4.163.80.0696290.9920.0420.0810.89198.1
4.16-4.763.70.066400.9940.0360.070.90498.3
4.76-63.70.0536590.9950.0320.0630.79799.2
6-503.50.0456640.9950.0280.0530.77498.1

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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: 2.21→29.488 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 21.7
RfactorNum. reflection% reflection
Rfree0.2198 618 4.99 %
Rwork0.164 --
obs0.1669 12377 96.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 112.36 Å2 / Biso mean: 36.5656 Å2 / Biso min: 15.76 Å2
Refinement stepCycle: final / Resolution: 2.21→29.488 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 30 18 2097
Biso mean--71.57 33.68 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092140
X-RAY DIFFRACTIONf_angle_d1.4082910
X-RAY DIFFRACTIONf_chiral_restr0.084299
X-RAY DIFFRACTIONf_plane_restr0.012376
X-RAY DIFFRACTIONf_dihedral_angle_d13.4071713
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.208-2.43010.26681480.20662831297995
2.4301-2.78150.27161510.20872907305896
2.7815-3.50350.27061580.18182961311997
3.5035-29.49070.16741610.13093060322199
Refinement TLS params.Method: refined / Origin x: -9.7255 Å / Origin y: -1.5831 Å / Origin z: 16.0082 Å
111213212223313233
T0.1699 Å2-0.0071 Å20.0005 Å2-0.1717 Å20.0053 Å2--0.183 Å2
L0.8488 °2-0.2005 °2-0.0813 °2-0.8922 °2-0.0675 °2--1.208 °2
S-0.0288 Å °-0.0168 Å °0.0375 Å °-0.0553 Å °0.0107 Å °-0.0314 Å °-0.0013 Å °0.0261 Å °-0.0001 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA4 - 261
2X-RAY DIFFRACTION1allB1 - 14
3X-RAY DIFFRACTION1allB15 - 18
4X-RAY DIFFRACTION1allC262
5X-RAY DIFFRACTION1allD1

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