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- PDB-8zq2: The crystal structure of PDE4D with isoaurostatin derivatives 2-1 -

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Basic information

Entry
Database: PDB / ID: 8zq2
TitleThe crystal structure of PDE4D with isoaurostatin derivatives 2-1
Components3',5'-cyclic-AMP phosphodiesterase 4D
KeywordsHYDROLASE / 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 / adrenergic receptor signaling pathway / heterocyclic compound binding / regulation of cell communication by electrical coupling involved in cardiac conduction / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-GMP phosphodiesterase activity / DARPP-32 events / 3',5'-cyclic-AMP phosphodiesterase activity / positive regulation of heart rate / cAMP-mediated signaling / cAMP binding / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cellular response to cAMP / cellular response to epinephrine stimulus / calcium channel regulator activity / calcium channel complex / positive regulation of interleukin-2 production / regulation of heart rate / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of type II interferon production / T cell receptor signaling pathway / ATPase binding / scaffold protein binding / G alpha (s) signalling events / nuclear membrane / 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: 2.10001445151 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

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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)116,3218
Polymers115,5172
Non-polymers8046
Water3,765209
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-102 kcal/mol
Surface area27260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.188, 80.167, 162.820
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-A1D8O / (3~{Z})-3-[(3-ethoxy-4-methoxy-phenyl)methylidene]-6-oxidanyl-1-benzofuran-2-one / LDC271 INHIBITOR


Mass: 312.317 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H16O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 209 / 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: 1.64 Å3/Da / Density % sol: 25.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting 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: Mar 18, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→23.67 Å / Num. obs: 45159 / % possible obs: 99.6 % / Redundancy: 4.9 % / Biso Wilson estimate: 19.012013584 Å2 / Rmerge(I) obs: 0.067 / Net I/σ(I): 14
Reflection shellResolution: 2.1→2.2 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.269 / Num. unique obs: 3667 / % possible all: 99.3

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Processing

Software
NameVersionClassification
REFMACV8refinement
PHENIX1.10_2155refinement
CrysalisPro171.39.46data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.10001445151→23.6696426253 Å / SU ML: 0.232876351763 / Cross valid method: NONE / σ(F): 1.34967131188 / Phase error: 23.9638574336
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.250849586213 2269 5.0310421286 %
Rwork0.209976908012 42831 -
obs0.212068923271 45100 99.5848789966 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.1148489754 Å2
Refinement stepCycle: LAST / Resolution: 2.10001445151→23.6696426253 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5248 0 50 209 5507
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00371608225015404
X-RAY DIFFRACTIONf_angle_d0.6636236164547342
X-RAY DIFFRACTIONf_chiral_restr0.0382345057893840
X-RAY DIFFRACTIONf_plane_restr0.0042665946166964
X-RAY DIFFRACTIONf_dihedral_angle_d15.24153700413276
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.100015-2.14560.284444862041380.2415160619072629X-RAY DIFFRACTION99.2467718795
2.1456-2.19550.2977826048571420.2443125021392614X-RAY DIFFRACTION99.1723641598
2.1955-2.25040.2879637942231490.2356598676532642X-RAY DIFFRACTION99.1826581379
2.2504-2.31120.3299832019741190.2236001296752631X-RAY DIFFRACTION99.2063492063
2.3112-2.37910.2674117921941470.2220243846932613X-RAY DIFFRACTION99.4236311239
2.3791-2.45580.2553670892271550.2204138102752625X-RAY DIFFRACTION99.5345506624
2.4558-2.54350.2940216535231430.2257370077482688X-RAY DIFFRACTION99.8589065256
2.5435-2.64520.2944662558291440.2260367580242658X-RAY DIFFRACTION100
2.6452-2.76550.2878133964411490.2256239922962675X-RAY DIFFRACTION100
2.7655-2.9110.2858825016891470.2245593666992660X-RAY DIFFRACTION100
2.911-3.0930.2480618388921340.219488073012692X-RAY DIFFRACTION100
3.093-3.33120.2656431839311240.2200696426962684X-RAY DIFFRACTION99.9288256228
3.3312-3.66540.2437773197111230.2099405152292736X-RAY DIFFRACTION99.8602864129
3.6654-4.19320.2227334968111480.1944684345582707X-RAY DIFFRACTION99.7205728257
4.1932-5.27340.2084261859351670.1765217717242724X-RAY DIFFRACTION99.586634516
5.2734-23.669640.183794186651400.1770443896422853X-RAY DIFFRACTION98.7137203166

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