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- PDB-4z1e: Carbonic anhydrase inhibitors: Design and synthesis of new hetero... -

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Basic information

Entry
Database: PDB / ID: 4z1e
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
6-methoxy-1-(4-sulfamoylbenzoyl)quinolinium / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.01 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)29,5673
Polymers29,1581
Non-polymers4092
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.390, 41.450, 72.290
Angle α, β, γ (deg.)90.000, 104.360, 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: 29157.863 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-DF5 / 6-methoxy-1-(4-sulfamoylbenzoyl)quinolinium


Mass: 343.377 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H15N2O4S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / 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: 2.11 Å3/Da / Density % sol: 41.71 %
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: 120 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.54179 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jun 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54179 Å / Relative weight: 1
ReflectionResolution: 2.009→70.031 Å / Num. all: 14518 / Num. obs: 14518 / % possible obs: 86.5 % / Redundancy: 3.8 % / Rpim(I) all: 0.043 / Rrim(I) all: 0.085 / Rsym value: 0.064 / Net I/av σ(I): 7.932 / Net I/σ(I): 10.9 / Num. measured all: 54802
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2-2.053.10.2592.825328160.1820.2593.567.3
2.05-2.113.80.2412.830348090.1630.2414.866.5
2.11-2.173.90.1853.8438811380.1260.1855.6100
2.17-2.233.70.1893.4413711250.1330.1895.597
2.23-2.3130.2121.814825000.1680.2124.845.7
2.31-2.393.90.1166.2413210610.0770.1168.1100
2.39-2.483.90.17.1406010420.0670.19100
2.48-2.583.90.097.837929780.0610.099.6100
2.58-2.693.90.0798.924516280.0540.07910.266.9
2.69-2.823.90.06810.236539320.0450.06811.8100
2.82-2.983.90.05811.833718560.0380.05813.1100
2.98-3.1640.0511331878050.0330.05115.2100
3.16-3.383.90.0431530407710.0280.04316.2100
3.38-3.653.70.0610.819475320.040.0615.772.9
3.65-3.993.30.0729.811813600.0510.07217.555
3.99-4.473.90.04213.123635990.0270.04219.299.7
4.47-5.1640.04213.421575430.0270.04219.6100
5.16-6.323.90.04512.617624530.0290.04517.9100
6.32-8.933.90.04912.214023630.0310.04918.2100
8.93-41.453.50.0512.27312070.0380.0518.996.4

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALA3.3.20data scaling
REFMAC5.6.0117refinement
PDB_EXTRACT3.15data extraction
REFMACphasing
RefinementResolution: 2.01→41.33 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.916 / WRfactor Rfree: 0.2393 / WRfactor Rwork: 0.1717 / FOM work R set: 0.7862 / SU B: 5.058 / SU ML: 0.144 / SU R Cruickshank DPI: 0.2544 / SU Rfree: 0.2109 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.254 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2437 732 5 %RANDOM
Rwork0.1719 ---
obs0.1754 13768 87.96 %-
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: 85.36 Å2 / Biso mean: 32.97 Å2 / Biso min: 18.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.53 Å20 Å20.09 Å2
2---0.22 Å20 Å2
3---0.8 Å2
Refinement stepCycle: final / Resolution: 2.01→41.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2041 0 25 191 2257
Biso mean--51.21 41.74 -
Num. residues----259
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.022137
X-RAY DIFFRACTIONr_bond_other_d0.0020.021443
X-RAY DIFFRACTIONr_angle_refined_deg1.5321.9592910
X-RAY DIFFRACTIONr_angle_other_deg0.97933527
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7475260
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.30924.69498
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.69115340
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.507157
X-RAY DIFFRACTIONr_chiral_restr0.0950.2304
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0212382
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02433
LS refinement shellResolution: 2.009→2.061 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.237 63 -
Rwork0.201 1009 -
all-1072 -
obs--90.31 %

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