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- PDB-4cq0: Cyclic secondary sulfonamides: unusually good inhibitors of cance... -

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Basic information

Entry
Database: PDB / ID: 4cq0
TitleCyclic secondary sulfonamides: unusually good inhibitors of cancer- related carbonic anhydrase enzymes
ComponentsCARBONIC ANHYDRASE 2
KeywordsLYASE / SACCHARIN / CLICK CHEMISTRY / DRUG DESIGN
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 / 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 / cyanamide hydratase activity / 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 / 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
FORMIC ACID / 6-amino-1,2-benzothiazol-3(2H)-one 1,1-dioxide / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.45 Å
AuthorsMoeker, J. / Peat, T.S. / Bornaghi, L.F. / Vullo, D. / Supuran, C.T. / Poulsen, S.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Cyclic Secondary Sulfonamides: Unusually Good Inhibitors of Cancer-Related Carbonic Anhydrase Enzymes.
Authors: Moeker, J. / Peat, T.S. / Bornaghi, L.F. / Vullo, D. / Supuran, C.T. / Poulsen, S.
History
DepositionFeb 10, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 16, 2014Provider: repository / Type: Initial release
Revision 1.1May 7, 2014Group: Database references
Revision 1.2May 15, 2019Group: Data collection / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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_database_status.status_code_sf / _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_conn.ptnr2_label_seq_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

Downloads & links

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Assembly

Deposited unit
A: CARBONIC ANHYDRASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,5994
Polymers29,2891
Non-polymers3103
Water4,396244
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.183, 41.210, 71.919
Angle α, β, γ (deg.)90.00, 104.64, 90.00
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
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PACA / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / 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-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-SXS / 6-amino-1,2-benzothiazol-3(2H)-one 1,1-dioxide


Mass: 198.199 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H6N2O3S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsLIGAND (SXS): SACCHARIN MOIETY

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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: 41.7 % / Description: NONE
Crystal growTemperature: 293 K / pH: 8.5
Details: THE PROTEIN WAS AT 14 MG/ML. THE RESERVOIR WAS 2.9 M AMMONIUM SULFATE, 100 MM TRIS PH 8.5. THE DROPS WERE 210 NL PROTEIN PLUS 110 NL RESERVOIR PLUS 40 NL COMPOUND. THE CRYSTALS GREW AT 20C.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.45→70 Å / Num. obs: 42055 / % possible obs: 98.8 % / Observed criterion σ(I): 0 / Redundancy: 7.3 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 12.8
Reflection shellResolution: 1.45→1.53 Å / Redundancy: 7 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 3.6 / % possible all: 97.4

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3ML2

3ml2


Resolution: 1.45→40.85 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.949 / SU B: 1.051 / SU ML: 0.041 / Cross valid method: THROUGHOUT / ESU R: 0.067 / ESU R Free: 0.07 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.19106 2118 5 %RANDOM
Rwork0.15732 ---
obs0.15903 39921 98.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 11.893 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å2-0 Å2-0.1 Å2
2--0.01 Å20 Å2
3----0.03 Å2
Refinement stepCycle: LAST / Resolution: 1.45→40.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2039 0 17 244 2300
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0250.0192309
X-RAY DIFFRACTIONr_bond_other_d0.0070.022155
X-RAY DIFFRACTIONr_angle_refined_deg2.4391.9633165
X-RAY DIFFRACTIONr_angle_other_deg1.04835020
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9585298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.06125.143105
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.76515397
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.878157
X-RAY DIFFRACTIONr_chiral_restr0.1590.2324
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0212727
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02530
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.7081.2691126
X-RAY DIFFRACTIONr_mcbond_other1.7091.2691127
X-RAY DIFFRACTIONr_mcangle_it2.3842.1511440
X-RAY DIFFRACTIONr_mcangle_other2.3832.1531441
X-RAY DIFFRACTIONr_scbond_it2.8071.5841183
X-RAY DIFFRACTIONr_scbond_other2.7941.5851180
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.0282.5021724
X-RAY DIFFRACTIONr_long_range_B_refined5.1547.6242825
X-RAY DIFFRACTIONr_long_range_B_other5.1557.6262826
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.355 147 -
Rwork0.352 2873 -
obs--96.79 %

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