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- PDB-3o57: Catalytic domain of human phosphodiesterase 4b2b in complex with ... -

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Basic information

Entry
Database: PDB / ID: 3o57
TitleCatalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4B
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PDE / HYDROLASE / PHOSPHODIESTERASE / cAMP Binding / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / neutrophil homeostasis / regulation of cardiac muscle cell contraction / gamma-tubulin binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / leukocyte migration / voltage-gated calcium channel complex ...negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / gamma-tubulin complex / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / neutrophil homeostasis / regulation of cardiac muscle cell contraction / gamma-tubulin binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / leukocyte migration / voltage-gated calcium channel complex / cAMP catabolic process / calcium channel regulator activity / excitatory synapse / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / cAMP binding / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / neutrophil chemotaxis / Z disc / positive regulation of type II interferon production / cellular response to xenobiotic stimulus / synaptic vesicle / T cell receptor signaling pathway / cellular response to lipopolysaccharide / transmembrane transporter binding / dendritic spine / postsynaptic density / centrosome / perinuclear region of cytoplasm / signal transduction / metal ion binding / nucleus / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. ...Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / 3'5'-cyclic nucleotide phosphodiesterase, conserved site / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily / 3'5'-cyclic nucleotide phosphodiesterase / 3'5'-cyclic nucleotide phosphodiesterase domain signature. / 3'5'-cyclic nucleotide phosphodiesterase domain profile. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
ARSENIC / Chem-ZG2 / 3',5'-cyclic-AMP phosphodiesterase 4B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsSomers, D.O. / Neu, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.
Authors: Mitchell, C.J. / Ballantine, S.P. / Coe, D.M. / Cook, C.M. / Delves, C.J. / Dowle, M.D. / Edlin, C.D. / Hamblin, J.N. / Holman, S. / Johnson, M.R. / Jones, P.S. / Keeling, S.E. / Kranz, M. / ...Authors: Mitchell, C.J. / Ballantine, S.P. / Coe, D.M. / Cook, C.M. / Delves, C.J. / Dowle, M.D. / Edlin, C.D. / Hamblin, J.N. / Holman, S. / Johnson, M.R. / Jones, P.S. / Keeling, S.E. / Kranz, M. / Lindvall, M. / Lucas, F.S. / Neu, M. / Solanke, Y.E. / Somers, D.O. / Trivedi, N.A. / Wiseman, J.O.
History
DepositionJul 28, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2011Provider: repository / Type: Initial release
Revision 1.1Sep 6, 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 / pdbx_struct_special_symmetry / struct_conn / struct_ref_seq_dif / 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.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_ref_seq_dif.details / _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: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,5058
Polymers40,5841
Non-polymers9217
Water5,350297
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.622, 94.907, 105.853
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number24
Space group name H-MI212121
Components on special symmetry positions
IDModelComponents
11A-96-

HOH

21A-128-

HOH

31A-583-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4B / DPDE4 / PDE32


Mass: 40583.949 Da / Num. of mol.: 1 / Fragment: Catalytic domain, UNP residues 324-675 / Mutation: S482A, S487A, S489A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4B, DPDE4 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q07343, 3',5'-cyclic-nucleotide phosphodiesterase

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Non-polymers , 6 types, 304 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ARS / ARSENIC / Arsenic


Mass: 74.922 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: As
#5: Chemical ChemComp-ZG2 / 5-[5-benzyl-4-(2-oxo-2-pyrrolidin-1-ylethyl)-1,3-oxazol-2-yl]-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine


Mass: 514.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H34N6O3
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 297 / 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: 2.74 Å3/Da / Density % sol: 55.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 14-18% PEG 3000, 10% Glycerol, 50mM Sodium Cacodylate pH 6.5, 100mM Sodium Acetate, 1M Sodium Chloride, 1% DMF, 5mM DTT, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Nov 20, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→29.794 Å / Num. obs: 30473 / % possible obs: 99.9 % / Redundancy: 5.4 % / Biso Wilson estimate: 30.3 Å2 / Rmerge(I) obs: 0.088 / Rsym value: 0.088 / Net I/σ(I): 15
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
2-2.115.40.5191.12383443910.51999.9
2.11-2.245.40.312.42255541440.31100
2.24-2.395.40.2222.82146939520.222100
2.39-2.585.40.1524.71976036340.152100
2.58-2.835.40.1175.71840333840.117100
2.83-3.165.40.0798.21664330730.079100
3.16-3.655.40.0648.71466827300.064100
3.65-4.475.30.069.21227423120.06100
4.47-6.325.20.0658.4947718260.065100
6.32-52.9264.70.0737.3478210270.07398.2

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Processing

Software
NameVersionClassificationNB
SCALA3.2.5data scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
MOSFLMdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3D3P

3d3p


Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.934 / WRfactor Rfree: 0.2292 / WRfactor Rwork: 0.1799 / Occupancy max: 1 / Occupancy min: 0.35 / FOM work R set: 0.8232 / SU B: 4.3 / SU ML: 0.118 / SU R Cruickshank DPI: 0.1638 / SU Rfree: 0.1591 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.159 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2399 1537 5 %RANDOM
Rwork0.1874 ---
obs0.1901 30445 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 83.8 Å2 / Biso mean: 39.2292 Å2 / Biso min: 15.19 Å2
Baniso -1Baniso -2Baniso -3
1--1.82 Å20 Å20 Å2
2---1.19 Å20 Å2
3---3.01 Å2
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2711 0 49 297 3057
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0212828
X-RAY DIFFRACTIONr_bond_other_d0.0010.021856
X-RAY DIFFRACTIONr_angle_refined_deg1.4061.9613838
X-RAY DIFFRACTIONr_angle_other_deg0.9863.0024539
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1755337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.27725140
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.33115491
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.2431513
X-RAY DIFFRACTIONr_chiral_restr0.0980.2429
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023129
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02550
X-RAY DIFFRACTIONr_mcbond_it2.01631681
X-RAY DIFFRACTIONr_mcbond_other0.6413673
X-RAY DIFFRACTIONr_mcangle_it3.12542726
X-RAY DIFFRACTIONr_scbond_it3.94951147
X-RAY DIFFRACTIONr_scangle_it5.65371111
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.314 95 -
Rwork0.279 2103 -
all-2198 -
obs--100 %

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