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- PDB-4z1n: Carbonic anhydrase inhibitors: Design and synthesis of new hetero... -

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Basic information

Entry
Database: PDB / ID: 4z1n
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-4KD / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.47 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 27, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
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)29,5133
Polymers29,0711
Non-polymers4422
Water3,315184
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.230, 41.295, 72.349
Angle α, β, γ (deg.)90.000, 104.510, 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-4KD / 4-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)carbonyl]benzenesulfonamide


Mass: 376.427 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N2O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 184 / 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: 2.1 Å3/Da / Density % sol: 41.45 %
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: 1.47→50 Å / Num. obs: 69904 / % possible obs: 86.6 % / Observed criterion σ(I): -3 / Redundancy: 1.3 % / Biso Wilson estimate: 16.287 Å2 / Rmerge F obs: 0.987 / Rmerge(I) obs: 0.109 / Rrim(I) all: 0.154 / Χ2: 1.261 / Net I/σ(I): 6.44 / Num. measured all: 90583
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
1.47-1.560.6660.442.241413413024106090.62181.5
1.56-1.670.6840.3742.91377612257103420.52884.4
1.67-1.80.7930.2733.95128621142297430.38585.3
1.8-1.970.8910.1765.81118551056690970.24886.1
1.97-2.20.9550.1117.6310710946883090.15787.8
2.2-2.540.9740.0839.099513838574720.11789.1
2.54-3.110.9880.05910.848138710964570.08490.8
3.11-4.380.9930.04513.346216547350450.06392.2
4.380.9910.04713.043379304128300.06693.1

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.47→39.93 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.214 / WRfactor Rwork: 0.1872 / FOM work R set: 0.8636 / SU B: 1.371 / SU ML: 0.052 / SU R Cruickshank DPI: 0.0803 / SU Rfree: 0.0794 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.08 / ESU R Free: 0.079 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2138 1995 5 %RANDOM
Rwork0.1886 ---
obs0.1899 37895 96.29 %-
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: 49.93 Å2 / Biso mean: 10.329 Å2 / Biso min: 4.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å2-0.18 Å2
2---0.8 Å20 Å2
3---0.69 Å2
Refinement stepCycle: final / Resolution: 1.47→39.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2036 0 23 195 2254
Biso mean--12.36 18.84 -
Num. residues----258
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.022152
X-RAY DIFFRACTIONr_bond_other_d0.0010.021453
X-RAY DIFFRACTIONr_angle_refined_deg1.8611.962937
X-RAY DIFFRACTIONr_angle_other_deg1.02733559
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8145267
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.70224.8100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.15115345
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.857157
X-RAY DIFFRACTIONr_chiral_restr0.1220.2308
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212410
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02435
LS refinement shellResolution: 1.469→1.507 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 137 -
Rwork0.269 2595 -
all-2732 -
obs--92.2 %

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