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- PDB-4pyx: Crystal structure of human carbonic anhydrase isozyme II with inh... -

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Basic information

Entry
Database: PDB / ID: 4pyx
TitleCrystal structure of human carbonic anhydrase isozyme II with inhibitor
ComponentsCarbonic anhydrase 2
KeywordsLYASE/LYASE INHIBITOR / drug design / carbonic anhydrase / benzenesulfonamide / metal-binding / 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 / 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 / apical part of cell / myelin sheath / extracellular exosome / zinc ion binding / plasma membrane / cytoplasm / cytosol
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-V90 / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / molecular replacement / Resolution: 1.8 Å
AuthorsSmirnov, A. / Manakova, E. / Grazulis, S.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.
Authors: Dudutiene, V. / Matuliene, J. / Smirnov, A. / Timm, D.D. / Zubriene, A. / Baranauskiene, L. / Morkunaite, V. / Smirnoviene, J. / Michailoviene, V. / Juozapaitiene, V. / Mickeviciute, A. / ...Authors: Dudutiene, V. / Matuliene, J. / Smirnov, A. / Timm, D.D. / Zubriene, A. / Baranauskiene, L. / Morkunaite, V. / Smirnoviene, J. / Michailoviene, V. / Juozapaitiene, V. / Mickeviciute, A. / Kazokaite, J. / Baksyte, S. / Kasiliauskaite, A. / Jachno, J. / Revuckiene, J. / Kisonaite, M. / Pilipuityte, V. / Ivanauskaite, E. / Milinaviciute, G. / Smirnovas, V. / Petrikaite, V. / Kairys, V. / Petrauskas, V. / Norvaisas, P. / Linge, D. / Gibieza, P. / Capkauskaite, E. / Zaksauskas, A. / Kazlauskas, E. / Manakova, E. / Grazulis, S. / Ladbury, J.E. / Matulis, D.
History
DepositionMar 28, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 28, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)30,0405
Polymers29,2891
Non-polymers7514
Water3,027168
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.022, 41.143, 71.519
Angle α, β, γ (deg.)90.000, 104.070, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 1 molecules A

#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
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

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Non-polymers , 5 types, 172 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#5: Chemical ChemComp-V90 / 2-(cyclooctylamino)-3,5,6-trifluoro-4-[(2-hydroxyethyl)sulfanyl]benzenesulfonamide


Mass: 412.491 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H23F3N2O3S2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / 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 Å3/Da / Density % sol: 38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7
Details: Crystallization buffer was 0.1M sodium BICINE, pH 9, 0.2 M ammonium sulfate and 2M sodium malonate pH 7 made from 1M sodium BICINE and 3.4M sodium malonate, VAPOR DIFFUSION, SITTING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Oct 30, 2012
RadiationMonochromator: VARIMAX-HF MIRROR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→25.222 Å / Num. obs: 21036 / % possible obs: 95.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Biso Wilson estimate: 18.529 Å2 / Rmerge(I) obs: 0.127 / Rsym value: 0.127 / Net I/σ(I): 9.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.8-1.93.70.4221.31078329430.42292
1.9-2.013.70.3331.61045828320.33393.1
2.01-2.153.70.2692981626630.26994.3
2.15-2.323.70.2152.6935825280.21594.6
2.32-2.553.70.1733.2874323670.17396.3
2.55-2.853.70.134.4789921280.1396
2.85-3.293.70.1025.4703419070.10297.3
3.29-4.033.70.0826.7605616560.08298.1
4.03-5.693.60.0756.9463312820.07598.4
5.69-25.223.40.0845.624887300.08497.4

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
MOSFLMdata reduction
SCALA3.2.19data scaling
PDB_EXTRACT3.006data extraction
HKL-3000data collection
MOLREPphasing
RefinementMethod to determine structure: molecular replacement
Starting model: PDB ENTRY 3HLJ

3hlj


Resolution: 1.8→25.22 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.923 / WRfactor Rfree: 0.227 / WRfactor Rwork: 0.175 / Occupancy max: 1 / Occupancy min: 0.01 / FOM work R set: 0.851 / SU R Cruickshank DPI: 0.163 / SU Rfree: 0.152 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.163 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.23 2095 10 %RANDOM
Rwork0.178 ---
all0.183 21026 --
obs0.183 21026 94.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 71.52 Å2 / Biso mean: 18.991 Å2 / Biso min: 7.02 Å2
Baniso -1Baniso -2Baniso -3
1-0.3 Å20 Å2-0.16 Å2
2---1.2 Å20 Å2
3---0.81 Å2
Refinement stepCycle: LAST / Resolution: 1.8→25.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2049 0 38 168 2255
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.022178
X-RAY DIFFRACTIONr_angle_refined_deg2.1371.9672957
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2955262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.59824.74799
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.70115359
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.848157
X-RAY DIFFRACTIONr_chiral_restr0.1450.2307
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.0211667
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.344 149 -
Rwork0.334 1303 -
all-1452 -
obs--90.81 %

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