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- PDB-6r6f: Crystal structure of human carbonic anhydrase isozyme II with 4-c... -

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Basic information

Entry
Database: PDB / ID: 6r6f
TitleCrystal structure of human carbonic anhydrase isozyme II with 4-chloro-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide
ComponentsCarbonic anhydrase 2
KeywordsLYASE / drug design / carbonic anhydrase / benzenesulfonamide / metal binding protein / 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 / regulation of intracellular pH / positive regulation of synaptic transmission, GABAergic / 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, 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
Similarity search - Domain/homology
Chem-EA3 / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.2 Å
AuthorsSmirnov, A. / Manakova, E. / Grazulis, S.
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Halogenated and di-substituted benzenesulfonamides as selective inhibitors of carbonic anhydrase isoforms.
Authors: Zaksauskas, A. / Capkauskaite, E. / Jezepcikas, L. / Linkuviene, V. / Paketuryte, V. / Smirnov, A. / Leitans, J. / Kazaks, A. / Dvinskis, E. / Manakova, E. / Grazulis, S. / Tars, K. / Matulis, D.
History
DepositionMar 27, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 25, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Apr 1, 2020Group: Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.page_first ..._citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Oct 6, 2021Group: Data collection / Database references / Structure summary
Category: database_2 / pdbx_contact_author / pdbx_database_proc
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Jan 24, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)29,8264
Polymers29,2891
Non-polymers5363
Water6,125340
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint2 kcal/mol
Surface area11710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.308, 41.749, 72.323
Angle α, β, γ (deg.)90.000, 104.190, 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: 29289.062 Da / Num. of mol.: 1 / Fragment: human carbonic anhydrase II
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CA2 / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P00918, carbonic anhydrase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1
Mutation: 4-chloro-2-cyclohexylsulfanyl-N-(2-hydroxyethyl)-5-sulfamoyl-benzamide
Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-EA3 / 4-chloranyl-2-cyclohexylsulfanyl-~{N}-(2-hydroxyethyl)-5-sulfamoyl-benzamide


Mass: 392.921 Da / Num. of mol.: 1 / Fragment: Zn / Source method: obtained synthetically / Formula: C15H21ClN2O4S2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Fragment: Dimethyl sulfoxide / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 340 / 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: 2

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Sample preparation

CrystalDensity Matthews: 2.11 Å3/Da / Density % sol: 41.82 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: Crystallization buffer: 0.1M sodium bicine (pH 9), 0.2M ammonium sulfate and 2M sodium malonate (pH 7)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 1.01 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.01 Å / Relative weight: 1
ReflectionResolution: 1.2→41.017 Å / Num. all: 71118 / Num. obs: 71118 / % possible obs: 93.2 % / Redundancy: 6 % / Rpim(I) all: 0.053 / Rrim(I) all: 0.133 / Rsym value: 0.118 / Net I/av σ(I): 2.431 / Net I/σ(I): 6.7 / Num. measured all: 427545
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.2-1.266.10.4341.5100160.2040.5110.43490.2
1.26-1.3460.3361.996560.160.3970.33692.4
1.34-1.4360.2582.490920.1220.3030.25892.1
1.43-1.555.70.1893.185590.0910.2220.18992.9
1.55-1.760.1543.578700.0710.1780.15492.9
1.7-1.96.20.143.673230.0630.1590.1495.4
1.9-2.196.10.1313.765310.0580.1460.13196.1
2.19-2.686.10.1174.254690.0520.1320.11795.6
2.68-3.795.80.1034.742810.0470.1150.10395.7
3.79-41.01760.095.623210.040.1010.0992.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMACrefinement
PDB_EXTRACT3.1data extraction
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3HLJ

3hlj


Resolution: 1.2→32.16 Å / Cor.coef. Fo:Fc: 0.98 / Cor.coef. Fo:Fc free: 0.958 / SU R Cruickshank DPI: 0.0437 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.044 / ESU R Free: 0.045
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.185 4509 6.3 %RANDOM
Rwork0.1457 ---
obs0.149 71102 92.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 123.11 Å2 / Biso mean: 19.0325 Å2 / Biso min: 6.82 Å2
Baniso -1Baniso -2Baniso -3
1-0.06 Å2-0 Å2-0.15 Å2
2---0.23 Å20 Å2
3---0.22 Å2
Refinement stepCycle: LAST / Resolution: 1.2→32.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2059 0 29 340 2428
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0122233
X-RAY DIFFRACTIONr_angle_refined_deg2.0491.653045
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0945276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.72223.853109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.15215369
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.373157
X-RAY DIFFRACTIONr_chiral_restr0.1410.2269
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.021759
X-RAY DIFFRACTIONr_mcbond_it2.7121.4231080
X-RAY DIFFRACTIONr_mcangle_it3.5222.1331364
X-RAY DIFFRACTIONr_scbond_it5.2111.7981153
X-RAY DIFFRACTIONr_rigid_bond_restr5.93632233
X-RAY DIFFRACTIONr_sphericity_free33.1915206
X-RAY DIFFRACTIONr_sphericity_bonded18.49352296
LS refinement shellResolution: 1.2→1.231 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rwork0.333 5021 -
obs--89.17 %

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