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- PDB-8zq1: The crystal structure of PDE4D with isoaurostatin derivatives 1-12 -

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Basic information

Entry
Database: PDB / ID: 8zq1
TitleThe crystal structure of PDE4D with isoaurostatin derivatives 1-12
Components3',5'-cyclic-AMP phosphodiesterase 4D
KeywordsHYDROLASE / Inhibitor
Function / homology
Function and homology information


signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding ...signaling receptor regulator activity / negative regulation of relaxation of cardiac muscle / negative regulation of heart contraction / 3',5'-cyclic-AMP phosphodiesterase / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of interleukin-5 production / establishment of endothelial barrier / regulation of cardiac muscle cell contraction / heterocyclic compound binding / beta-2 adrenergic receptor binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / adrenergic receptor signaling pathway / cAMP catabolic process / regulation of cell communication by electrical coupling involved in cardiac conduction / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / DARPP-32 events / : / positive regulation of heart rate / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / calcium channel complex / positive regulation of interleukin-2 production / cellular response to epinephrine stimulus / regulation of heart rate / cellular response to cAMP / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / calcium channel regulator activity / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / nuclear membrane / G alpha (s) signalling events / transmembrane transporter binding / cilium / apical plasma membrane / centrosome / enzyme binding / nucleoplasm / metal ion binding / membrane / 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
: / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.20000099253 Å
AuthorsHuang, Y.-Y. / Luo, H.-B.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)22277019 China
CitationJournal: Chin.Chem.Lett. / Year: 2024
Title: Structure-based optimization of isoaurostatin as novel PDE4 inhibitors with anti-fibrotic effects
Authors: Huang, Y.Y. / Luo, X. / Zhang, K. / Liang, Y. / Zhang, F. / Liao, G. / Xie, S. / Huang, P.L. / Hou, S. / Zhou, Q. / Zou, Y. / Luo, H.B.
History
DepositionMay 31, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2025Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 3',5'-cyclic-AMP phosphodiesterase 4D
B: 3',5'-cyclic-AMP phosphodiesterase 4D
hetero molecules


Theoretical massNumber of molelcules
Total (without water)116,2938
Polymers115,5172
Non-polymers7766
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1970 Å2
ΔGint-102 kcal/mol
Surface area27880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.662, 80.321, 163.032
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 57758.402 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 (bacteria)
References: UniProt: Q08499, 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-A1D8N / (3~{E})-3-[(3,4-dimethoxyphenyl)methylidene]-6-oxidanyl-1-benzofuran-2-one


Mass: 298.290 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H14O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 1.63 Å3/Da / Density % sol: 24.73 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M HEPES (pH 7.4), 0.1M MgCl2, 15% PEG3350, 10% isopropanol, 25% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-3000 / Detector: PIXEL / Date: Nov 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→25.747 Å / Num. obs: 38499 / % possible obs: 98.05 % / Redundancy: 4.5 % / Biso Wilson estimate: 23.7794087996 Å2 / Rmerge(I) obs: 0.081 / Net I/σ(I): 14.4
Reflection shellResolution: 2.2→2.3 Å / Rmerge(I) obs: 0.296 / Mean I/σ(I) obs: 3.8 / Num. unique obs: 3834 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMACv8.0refinement
PHENIX1.10-2155refinement
CrysalisPro171.39.46data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.20000099253→25.7468658448 Å / SU ML: 0.292297352011 / Cross valid method: NONE / σ(F): 1.38186185174 / Phase error: 26.7150564328
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.266367264916 2006 5.21174330995 %
Rwork0.226697470781 36484 -
obs0.22879028954 38490 98.0287286064 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.9823414454 Å2
Refinement stepCycle: LAST / Resolution: 2.20000099253→25.7468658448 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5220 0 48 156 5424
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003049682777245375
X-RAY DIFFRACTIONf_angle_d0.6563009118637305
X-RAY DIFFRACTIONf_chiral_restr0.0375730076302837
X-RAY DIFFRACTIONf_plane_restr0.00371915592977982
X-RAY DIFFRACTIONf_dihedral_angle_d19.32888166372003
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.200001-2.2550.33910158721600.2981193690462572X-RAY DIFFRACTION99.9268471105
2.255-2.31590.3433619337731330.275366641972647X-RAY DIFFRACTION99.9281092739
2.3159-2.3840.30276685621500.2703448296312616X-RAY DIFFRACTION99.9277456647
2.384-2.46090.2976527041581440.2585824354072602X-RAY DIFFRACTION100
2.4609-2.54880.348665922661430.258059726352631X-RAY DIFFRACTION100
2.5488-2.65070.3007663197141300.2527463340132646X-RAY DIFFRACTION99.5338831122
2.6507-2.77130.3093575180681400.2335379191052611X-RAY DIFFRACTION98.9568345324
2.7713-2.91720.3148148296371290.2452799140652608X-RAY DIFFRACTION98.8800578035
2.9172-3.09970.32052735231490.249362789762609X-RAY DIFFRACTION98.3594864479
3.0997-3.33850.2570256094511430.2354862651612593X-RAY DIFFRACTION97.8540772532
3.3385-3.67360.2741460357061330.2204315247022592X-RAY DIFFRACTION96.8028419183
3.6736-4.20320.2338110991291440.208104208822572X-RAY DIFFRACTION96.2437987243
4.2032-5.28810.2054827521281470.1808860079392586X-RAY DIFFRACTION95.0939457203
5.2881-25.7460.2020517318721610.1824553169142599X-RAY DIFFRACTION91.7248255234

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