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- PDB-6ic2: Polypharmacology of Epacadostat: a Potent and Selective Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 6ic2
TitlePolypharmacology of Epacadostat: a Potent and Selective Inhibitor of the Tumor Associated Carbonic Anhydrases IX and XII
ComponentsCarbonic anhydrase 2
KeywordsLIGASE / Inhibitor / Carbonic anhydrase II
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 / angiotensin-activated signaling pathway ...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 / angiotensin-activated signaling pathway / positive regulation of synaptic transmission, GABAergic / regulation of intracellular pH / morphogenesis of an epithelium / 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-BBJ / Carbonic anhydrase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.15 Å
AuthorsAngeli, A. / Ferraroni, M. / Supuran, C.T. / Carta, F.
CitationJournal: Chem.Commun.(Camb.) / Year: 2019
Title: Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII.
Authors: Angeli, A. / Ferraroni, M. / Nocentini, A. / Selleri, S. / Gratteri, P. / Supuran, C.T. / Carta, F.
History
DepositionDec 1, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 15, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)29,7933
Polymers29,2891
Non-polymers5042
Water3,531196
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.418, 41.385, 72.320
Angle α, β, γ (deg.)90.00, 104.54, 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) / 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-BBJ / N-(3-bromo-4-fluorophenyl)-N'-hydroxy-4-{[2-(sulfamoylamino)ethyl]amino}-1,2,5-oxadiazole-3-carboximidamide / Epacadostat


Mass: 438.233 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H13BrFN7O4S / Comment: inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 196 / 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: 41.37 %
Crystal growTemperature: 296 K / Method: vapor diffusion / pH: 8 / Details: 1.7 M sodium citrate, 50 mM Tris pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: BM30A / Wavelength: 0.826 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.826 Å / Relative weight: 1
ReflectionResolution: 1.15→41.06 Å / Num. obs: 81956 / % possible obs: 94.9 % / Redundancy: 3.26 % / Net I/σ(I): 11.39
Reflection shellResolution: 1.15→1.19 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0218refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementResolution: 1.15→41.06 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.954 / SU B: 3.422 / SU ML: 0.062 / Cross valid method: THROUGHOUT / ESU R: 0.059 / ESU R Free: 0.055 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26841 3937 4.8 %RANDOM
Rwork0.24251 ---
obs0.2437 77585 94.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 19.944 Å2
Baniso -1Baniso -2Baniso -3
1--0.7 Å2-0 Å20.23 Å2
2---1.48 Å20 Å2
3---1.82 Å2
Refinement stepCycle: 1 / Resolution: 1.15→41.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2059 0 26 196 2281
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0192198
X-RAY DIFFRACTIONr_bond_other_d0.0020.021989
X-RAY DIFFRACTIONr_angle_refined_deg1.1661.9572997
X-RAY DIFFRACTIONr_angle_other_deg0.734652
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8835276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.94524.54599
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.70615364
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.685157
X-RAY DIFFRACTIONr_chiral_restr0.0660.2313
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0212455
X-RAY DIFFRACTIONr_gen_planes_other0.0060.02447
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_it1.9291.8231056
X-RAY DIFFRACTIONr_mcbond_other1.9281.8261057
X-RAY DIFFRACTIONr_mcangle_it2.362.731325
X-RAY DIFFRACTIONr_mcangle_other2.3222.7281325
X-RAY DIFFRACTIONr_scbond_it3.9912.0681142
X-RAY DIFFRACTIONr_scbond_other3.9912.0681143
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.6592.9991665
X-RAY DIFFRACTIONr_long_range_B_refined4.41322.4972497
X-RAY DIFFRACTIONr_long_range_B_other4.41722.4992498
X-RAY DIFFRACTIONr_rigid_bond_restr29.16934187
X-RAY DIFFRACTIONr_sphericity_free23.0945101
X-RAY DIFFRACTIONr_sphericity_bonded17.62754212
LS refinement shellResolution: 1.15→1.18 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.541 264 -
Rwork0.526 5233 -
obs--86.57 %

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