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- PDB-5ohj: Human phosphodiesterase 4B catalytic domain in complex with a pyr... -

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Basic information

Entry
Database: PDB / ID: 5ohj
TitleHuman phosphodiesterase 4B catalytic domain in complex with a pyrrolidinyl inhibitor.
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4B
KeywordsHYDROLASE / human phosphodiesterase 4B / pyrrolidinyl inhibitor / PDE4B
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 / synaptic vesicle / cellular response to xenobiotic stimulus / 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
Chem-9VE / 3',5'-cyclic-AMP phosphodiesterase 4B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsRizzi, A. / Carzaniga, L. / Armani, E.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases.
Authors: Carzaniga, L. / Amari, G. / Rizzi, A. / Capaldi, C. / De Fanti, R. / Ghidini, E. / Villetti, G. / Carnini, C. / Moretto, N. / Facchinetti, F. / Caruso, P. / Marchini, G. / Battipaglia, L. / ...Authors: Carzaniga, L. / Amari, G. / Rizzi, A. / Capaldi, C. / De Fanti, R. / Ghidini, E. / Villetti, G. / Carnini, C. / Moretto, N. / Facchinetti, F. / Caruso, P. / Marchini, G. / Battipaglia, L. / Patacchini, R. / Cenacchi, V. / Volta, R. / Amadei, F. / Pappani, A. / Capacchi, S. / Bagnacani, V. / Delcanale, M. / Puccini, P. / Catinella, S. / Civelli, M. / Armani, E.
History
DepositionJul 17, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 13, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 10, 2018Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Apr 3, 2019Group: Data collection / Source and taxonomy
Category: database_PDB_rev / database_PDB_rev_record / entity_src_gen
Item: _entity_src_gen.pdbx_host_org_cell_line

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,5248
Polymers96,8852
Non-polymers1,6396
Water2,972165
1
A: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,2624
Polymers48,4431
Non-polymers8193
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,2624
Polymers48,4431
Non-polymers8193
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.270, 55.730, 225.560
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 48442.699 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4B, DPDE4 / Plasmid: pFastbac1:PDE4B UCR / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q07343, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-9VE / [(1~{S})-2-[3,5-bis(chloranyl)-1-oxidanyl-pyridin-1-ium-4-yl]-1-[4-[bis(fluoranyl)methoxy]-3-(cyclopropylmethoxy)phenyl]ethyl] (2~{S})-1-[3-(dimethylcarbamoyl)phenyl]sulfonylpyrrolidine-2-carboxylate


Mass: 729.595 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H34Cl2F2N3O8S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 165 / 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: 1.8 Å3/Da / Density % sol: 31.5 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: Drops comprised 2microliters protein solution mixed with reservoir buffer consisting of 100mM sodium acetate pH 4.5, 14% PEG400 and 50mM calcium acetate. After 2 days they were streak seeded ...Details: Drops comprised 2microliters protein solution mixed with reservoir buffer consisting of 100mM sodium acetate pH 4.5, 14% PEG400 and 50mM calcium acetate. After 2 days they were streak seeded with crystals obtained from rolipram complex seed stock. Crystals, up to 100 microns in largest dimension, grew from precipitate after 1-2 weeks. Crystals were transferred to a cryoprotectant solution (100mM sodium acetate pH 4.5, 14% PEG400, 50mM calcium acetate and 20% glycerol) then flash-frozen prior to X-ray data collection.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Oct 31, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.51→29.61 Å / Num. obs: 85681 / % possible obs: 77.7 % / Redundancy: 6.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.046 / Rpim(I) all: 0.041 / Net I/σ(I): 22.4
Reflection shellResolution: 1.51→1.55 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.467 / Mean I/σ(I) obs: 2.6 / Num. unique obs: 2246 / CC1/2: 0.791 / Rpim(I) all: 0.149 / % possible all: 28.3

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: dimer of the catalytic domain of PDE4D

Resolution: 1.6→29.61 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.945 / SU B: 3.208 / SU ML: 0.056 / Cross valid method: THROUGHOUT / ESU R: 0.103 / ESU R Free: 0.099 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.21153 4027 5 %RANDOM
Rwork0.1841 ---
obs0.18549 76169 86.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 22.688 Å2
Baniso -1Baniso -2Baniso -3
1--0.18 Å20 Å2-0 Å2
2--0.4 Å2-0 Å2
3----0.22 Å2
Refinement stepCycle: 1 / Resolution: 1.6→29.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5421 0 100 165 5686
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0195652
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.881.9427678
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8095673
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.50724.947281
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.715989
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.021527
X-RAY DIFFRACTIONr_chiral_restr0.1310.2866
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.024437
X-RAY DIFFRACTIONr_gen_planes_other
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.294 143 -
Rwork0.255 2725 -
obs--42.27 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.4536-0.0469-0.28620.6214-0.05921.402-0.01390.0417-0.06470.0359-0.00690.0330.0115-0.03550.02080.0032-0.0035-0.00020.0643-0.02380.0276-20.6811-15.00618.0595
20.8089-0.0707-0.0761.3662-0.09421.36990.0145-0.0020.0805-0.01020.01850.0024-0.1435-0.0137-0.0330.04440.00190.0090.091-0.01960.03293.69568.596738.3654
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A323 - 744
2X-RAY DIFFRACTION2B324 - 745

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