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- PDB-4z0q: Carbonic anhydrase inhibitors: Design and synthesis of new hetero... -

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Basic information

Entry
Database: PDB / ID: 4z0q
TitleCarbonic anhydrase inhibitors: Design and synthesis of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms (hCA VII, hCA IX, and hCA XIV)
ComponentsCarbonic anhydrase 2
KeywordsLYASE / Carbonate dehydratase II / Carbonic anhydrase C / Carbonic anhydrase II / CA-II / Carbonate dehydratase II- 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-4K9 / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.45 Å
AuthorsBrynda, J. / Pospisilova, K. / Rezacova, P. / Pachl, P.
Funding support Czech Republic, 2items
OrganizationGrant numberCountry
GACRGA15-05677S Czech Republic
Technology Agency of the Czech RepublicTE01020028 Czech Republic
CitationJournal: Eur.J.Med.Chem. / Year: 2015
Title: Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms.
Authors: Buemi, M.R. / De Luca, L. / Ferro, S. / Bruno, E. / Ceruso, M. / Supuran, C.T. / Pospisilova, K. / Brynda, J. / Rezacova, P. / Gitto, R.
History
DepositionMar 26, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Carbonic anhydrase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,4533
Polymers29,0711
Non-polymers3822
Water3,549197
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.273, 41.697, 72.407
Angle α, β, γ (deg.)90.000, 104.630, 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: 29070.785 Da / Num. of mol.: 1
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-4K9 / 4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)benzenesulfonamide


Mass: 316.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16N2O3S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 197 / 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: 2.12 Å3/Da / Density % sol: 42.09 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.8 / Details: 50mM Tris-HCl, 1,6 M Sodium Citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.2 / Wavelength: 0.91841 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.45→50 Å / Num. obs: 43348 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 3.7 % / Biso Wilson estimate: 18.366 Å2 / Rmerge F obs: 0.998 / Rmerge(I) obs: 0.079 / Rrim(I) all: 0.092 / Χ2: 0.933 / Net I/σ(I): 11.61 / Num. measured all: 160778
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Highest resolution (Å)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
1.45-1.540.7350.562.3825212695168860.65899.1
1.54-1.640.8640.3713.5524322656865560.43699.8
1.64-1.780.9340.2575.0822809612861220.30199.9
1.78-1.940.9760.1518.1921077563656280.17799.9
1.94-2.170.990.09113.2219188510550980.10799.9
2.17-2.510.9950.06717.7516977453945260.07899.7
2.51-3.070.9970.05122.8814359384238420.059100
3.07-4.330.9980.03531.9510994300129950.04199.8
4.330.9980.0332.535840172916950.03698

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3VBD

3vbd


Resolution: 1.45→40.9 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.957 / WRfactor Rfree: 0.1781 / WRfactor Rwork: 0.1406 / FOM work R set: 0.8948 / SU B: 2.204 / SU ML: 0.042 / SU R Cruickshank DPI: 0.0713 / SU Rfree: 0.0674 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.071 / ESU R Free: 0.067 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1914 2168 5 %RANDOM
Rwork0.1464 ---
obs0.1486 41181 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 62.03 Å2 / Biso mean: 12.374 Å2 / Biso min: 5.17 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å20.12 Å2
2---0.02 Å20 Å2
3----0.02 Å2
Refinement stepCycle: final / Resolution: 1.45→40.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2053 0 23 197 2273
Biso mean--12.26 21.61 -
Num. residues----258
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.022208
X-RAY DIFFRACTIONr_bond_other_d0.0020.021513
X-RAY DIFFRACTIONr_angle_refined_deg1.8291.9833007
X-RAY DIFFRACTIONr_angle_other_deg2.36133692
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5815264
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.28724.64699
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.82415355
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.589157
X-RAY DIFFRACTIONr_chiral_restr0.1350.2304
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212433
X-RAY DIFFRACTIONr_gen_planes_other0.0080.02452
X-RAY DIFFRACTIONr_rigid_bond_restr10.43232127
X-RAY DIFFRACTIONr_sphericity_bonded9.93852067
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.245 150 -
Rwork0.184 2854 -
all-3004 -
obs--98.01 %

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