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- PDB-8k4c: Crystal structure of PDE4D complexed with ethaverine hydrochloride -

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Basic information

Entry
Database: PDB / ID: 8k4c
TitleCrystal structure of PDE4D complexed with ethaverine hydrochloride
ComponentscAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4D / Complex / Ethaverine hydrochloride / Inhibitor
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-VIC / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsLiu, J.Y. / Li, M.J. / Xu, Y.C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Drug repurposing and structure-based discovery of new PDE4 and PDE5 inhibitors.
Authors: Liu, J. / Zhang, X. / Chen, G. / Shao, Q. / Zou, Y. / Li, Z. / Su, H. / Li, M. / Xu, Y.
History
DepositionJul 17, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)81,2259
Polymers80,1932
Non-polymers1,0327
Water2,018112
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1980 Å2
ΔGint-102 kcal/mol
Surface area27130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.691, 79.863, 162.862
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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) / Strain (production host): BL21(DE3)
References: UniProt: Q08499, 3',5'-cyclic-AMP phosphodiesterase

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Non-polymers , 5 types, 119 molecules

#2: Chemical ChemComp-VIC / 1-[(3,4-diethoxyphenyl)methyl]-6,7-diethoxy-isoquinoline


Mass: 395.491 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H29NO4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ZN / ZINC ION


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


Mass: 62.068 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C2H6O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 2.47 Å3/Da / Density % sol: 50.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 0.1 M HEPES, 0.2 M MgCl2, 10 % (v/v) Isopropanol, 30 % (v/v) Ethylene glycol, 18 % (w/v) 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: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 20, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 44763 / % possible obs: 100 % / Redundancy: 13 % / CC1/2: 0.994 / CC star: 0.999 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.048 / Rrim(I) all: 0.174 / Χ2: 0.448 / Net I/σ(I): 2.2 / Num. measured all: 582646
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2CC starRpim(I) allRrim(I) allΧ2
2.1-2.1813.10.84543850.8590.9610.240.8790.412
2.18-2.26130.77144190.8920.9710.220.8020.452
2.26-2.3713.30.55843970.9380.9840.1580.580.426
2.37-2.4913.50.45344120.9610.990.1260.470.436
2.49-2.6513.10.3644540.9730.9930.1030.3740.449
2.65-2.8513.20.27344390.9830.9960.0780.2840.464
2.85-3.14130.19744560.990.9980.0560.2050.476
3.14-3.5913.40.13345060.9960.9990.0380.1380.483
3.59-4.5212.50.08945320.9970.9990.0260.0930.488
4.52-5012.10.06947630.9980.9990.020.0720.397

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Processing

Software
NameVersionClassification
PHENIX(1.17.1_3660)refinement
HKL-3000data scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→39.93 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 26.06 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2691 2208 4.94 %
Rwork0.2353 --
obs0.2369 44672 99.93 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→39.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5114 0 62 112 5288
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0025299
X-RAY DIFFRACTIONf_angle_d0.4787218
X-RAY DIFFRACTIONf_dihedral_angle_d5.257741
X-RAY DIFFRACTIONf_chiral_restr0.036837
X-RAY DIFFRACTIONf_plane_restr0.005925
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.27271390.26572602X-RAY DIFFRACTION99
2.15-2.20.28351280.26382606X-RAY DIFFRACTION100
2.2-2.250.36541310.27742580X-RAY DIFFRACTION100
2.25-2.310.26471350.26792671X-RAY DIFFRACTION100
2.31-2.380.26361440.26092604X-RAY DIFFRACTION100
2.38-2.460.30951340.24922622X-RAY DIFFRACTION100
2.46-2.550.28851470.25542614X-RAY DIFFRACTION100
2.55-2.650.27831190.25832665X-RAY DIFFRACTION100
2.65-2.770.27161440.24322630X-RAY DIFFRACTION100
2.77-2.910.2971260.25262648X-RAY DIFFRACTION100
2.91-3.10.28341590.25162627X-RAY DIFFRACTION100
3.1-3.330.29371370.23992667X-RAY DIFFRACTION100
3.34-3.670.25171400.23322663X-RAY DIFFRACTION100
3.67-4.20.27191340.22012691X-RAY DIFFRACTION100
4.2-5.290.24091290.20382746X-RAY DIFFRACTION100
5.29-39.930.23461620.20952828X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 19.7988 Å / Origin y: 3.0343 Å / Origin z: 46.5671 Å
111213212223313233
T0.1571 Å20.034 Å20.0331 Å2-0.1761 Å20.001 Å2--0.2022 Å2
L0.2601 °2-0.3949 °2-0.2905 °2-0.7749 °20.736 °2--2.0509 °2
S-0.0942 Å °-0.0752 Å °0.0701 Å °0.1346 Å °0.1478 Å °-0.0205 Å °0.2459 Å °0.1774 Å °-0.0207 Å °
Refinement TLS groupSelection details: all

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