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- PDB-7cbq: Crystal structure of PDE4D catalytic domain in complex with Apremilast -

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Basic information

Entry
Database: PDB / ID: 7cbq
TitleCrystal structure of PDE4D catalytic domain in complex with Apremilast
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4D / inhibitor / Complex structure / METAL BINDING PROTEIN
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...signaling receptor regulator activity / negative regulation of heart contraction / negative regulation of relaxation of cardiac muscle / 3',5'-cyclic-AMP phosphodiesterase / positive regulation of interleukin-5 production / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / heterocyclic compound binding / positive regulation of heart rate / adrenergic receptor signaling pathway / regulation of cell communication by electrical coupling involved in cardiac conduction / negative regulation of peptidyl-serine phosphorylation / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-GMP phosphodiesterase activity / calcium channel regulator activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cAMP-mediated signaling / calcium channel complex / cellular response to epinephrine stimulus / positive regulation of interleukin-2 production / regulation of heart rate / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / transmembrane transporter binding / apical plasma membrane / centrosome / perinuclear region of cytoplasm / enzyme binding / membrane / nucleus / metal ion binding / plasma membrane / cytosol
Similarity search - Function
Phosphodiesterase 4 upstream conserved regions (UCR) / Phosphodiesterase 4 upstream conserved regions (UCR) / 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.
Similarity search - Domain/homology
Chem-A9L / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.59 Å
AuthorsZhang, X.L. / Xu, Y.C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21877122 China
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.
Authors: Zhang, R. / Li, H. / Zhang, X. / Li, J. / Su, H. / Lu, Q. / Dong, G. / Dou, H. / Fan, C. / Gu, Z. / Mu, Q. / Tang, W. / Xu, Y. / Liu, H.
History
DepositionJun 13, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 27, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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 4D
B: cAMP-specific 3',5'-cyclic phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,00020
Polymers80,1932
Non-polymers1,80718
Water7,332407
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-77 kcal/mol
Surface area27040 Å2
Unit cell
Length a, b, c (Å)58.787, 80.221, 163.468
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein cAMP-specific 3',5'-cyclic phosphodiesterase 4D / PDE4D / DPDE3 / PDE43


Mass: 40096.355 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE4D, DPDE3 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 425 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-A9L / N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}acetamide


Mass: 460.500 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N2O7S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.4 Å3/Da / Density % sol: 48.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, 0.2 M MgCl2, 10% isopropanol, 30% EG, 18% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 23, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.58→50 Å / Num. obs: 104898 / % possible obs: 99.9 % / Redundancy: 12.7 % / Rmerge(I) obs: 0.087 / Rpim(I) all: 0.025 / Rrim(I) all: 0.091 / Χ2: 0.968 / Net I/σ(I): 7.5 / Num. measured all: 1332411
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.58-1.61100.64851130.930.2040.6810.84399.4
1.61-1.6411.10.60651870.9420.1840.6350.88699.7
1.64-1.6711.70.5651860.9580.1670.5850.87100
1.67-1.712.20.50651790.9650.1490.5280.894100
1.7-1.7412.60.46651810.9640.1360.4860.911100
1.74-1.7812.30.38551950.9760.1130.4010.963100
1.78-1.8212.60.33551950.9780.0980.350.993100
1.82-1.8713.60.29852020.9830.0840.311.01100
1.87-1.9313.70.25152030.9860.070.2611.04100
1.93-1.9913.50.21152210.9890.060.221.087100
1.99-2.0613.20.17852120.9920.0510.1851.111100
2.06-2.1412.50.15252230.9930.0450.1591.181100
2.14-2.24130.13552190.9940.0390.141.17100
2.24-2.3613.60.12152600.9940.0340.1261.139100
2.36-2.5113.50.10852480.9950.0310.1121.098100
2.51-2.7130.09852510.9960.0280.1021.05100
2.7-2.9712.90.08753090.9960.0250.0910.985100
2.97-3.413.60.07553290.9970.0210.0780.843100
3.4-4.2912.60.06453680.9980.0190.0670.714100
4.29-5012.60.05456170.9980.0160.0570.51499.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data scaling
PHASERphasing
PHENIX1.17.1-3660refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6INK

6ink


Resolution: 1.59→45.07 Å / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 19.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2051 5070 4.99 %
Rwork0.1764 96515 -
obs0.1779 101585 96.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 69.59 Å2 / Biso mean: 20.2052 Å2 / Biso min: 4.15 Å2
Refinement stepCycle: final / Resolution: 1.59→45.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5198 0 113 407 5718
Biso mean--26.24 29.37 -
Num. residues----651
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.59-1.60.24711020.20191921202358
1.6-1.620.22091250.19762571269678
1.62-1.640.22191340.1922775290983
1.64-1.660.21531630.20132874303788
1.66-1.680.23861510.19663055320691
1.68-1.710.21471610.19823146330796
1.71-1.730.22541500.19253221337197
1.73-1.760.20691620.19813282344499
1.76-1.790.23981730.19393308348199
1.79-1.820.241820.193632683450100
1.82-1.850.22991880.192733193507100
1.85-1.880.24911880.191433093497100
1.88-1.920.20061640.18133143478100
1.92-1.960.21961850.182433423527100
1.96-20.22211880.180932473435100
2-2.040.20841770.179633223499100
2.04-2.10.19711850.173733203505100
2.1-2.150.18151610.172233243485100
2.15-2.220.21241870.166333193506100
2.22-2.290.1761730.168233343507100
2.29-2.370.21351590.174233853544100
2.37-2.460.22041710.167833213492100
2.46-2.580.19411900.176233333523100
2.58-2.710.22931670.18133573524100
2.71-2.880.19881750.172433783553100
2.88-3.10.21271990.177633723571100
3.1-3.420.19331740.175533843558100
3.42-3.910.19461880.175733973585100
3.91-4.920.1771560.152734773633100
4.92-45.070.19211920.17473540373298
Refinement TLS params.Method: refined / Origin x: 78.9878 Å / Origin y: 163.4871 Å / Origin z: 46.7132 Å
111213212223313233
T0.0446 Å20.0116 Å20.0211 Å2-0.057 Å20.0098 Å2--0.0867 Å2
L0.1499 °2-0.1288 °20.0158 °2-0.3151 °20.1144 °2--1.095 °2
S-0.0473 Å °-0.0436 Å °0.0148 Å °0.0765 Å °0.0694 Å °0.021 Å °0.0656 Å °0.0848 Å °-0.005 Å °
Refinement TLS groupSelection details: all

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