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- PDB-7xab: Crystal structure of PDE4D catalytic domain complexed with compou... -

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Basic information

Entry
Database: PDB / ID: 7xab
TitleCrystal structure of PDE4D catalytic domain complexed with compound 22d
ComponentsIsoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D
KeywordsHYDROLASE / PDE4 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-AWI / 3',5'-cyclic-AMP phosphodiesterase 4D
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.00067450802 Å
AuthorsHuang, Y.-Y. / He, X. / Luo, H.-B.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82003576 China
National Natural Science Foundation of China (NSFC)21877134 China
National Natural Science Foundation of China (NSFC)22077143 China
CitationJournal: Eur.J.Med.Chem. / Year: 2022
Title: Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.
Authors: Liu, H. / Wang, Q. / Huang, Y. / Deng, J. / Xie, X. / Zhu, J. / Yuan, Y. / He, Y.M. / Huang, Y.Y. / Luo, H.B. / He, X.
History
DepositionMar 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)117,0068
Polymers115,7192
Non-polymers1,2876
Water8,521473
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4030 Å2
ΔGint-110 kcal/mol
Surface area27630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.622, 80.410, 162.952
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 Isoform 3 of cAMP-specific 3',5'-cyclic phosphodiesterase 4D / DPDE3 / PDE43


Mass: 57859.504 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-AWI / 9-(cyclopropylmethoxy)-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-enyl)-5-(pyridin-4-ylmethoxy)pyrano[3,2-b]xanthen-6-one


Mass: 553.645 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H35NO6 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 473 / Source method: isolated from a natural source / Formula: H2O
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

Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES (pH 7.4), 0.1 M MgCl2, 15% PEG3350, 10% isopropanol, and 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: Jul 12, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→23.684952 Å / Num. obs: 52475 / % possible obs: 99.2 % / Redundancy: 4.2 % / Biso Wilson estimate: 18.9366220336 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 22.6
Reflection shellResolution: 2→2.1 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.243 / Mean I/σ(I) obs: 4.2 / Num. unique obs: 5169 / % possible all: 99.1

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
CrysalisProdata reduction
CrysalisProdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WQA

5wqa


Resolution: 2.00067450802→23.6849517665 Å / SU ML: 0.242816824763 / Cross valid method: NONE / σ(F): 1.37204272397 / Phase error: 23.6298748882
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.247086538266 2563 4.89019480643 %
Rwork0.19539501064 49848 -
obs0.197869925293 52411 99.2106458696 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 23.0365486267 Å2
Refinement stepCycle: LAST / Resolution: 2.00067450802→23.6849517665 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5230 0 86 473 5789
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007847549040335428
X-RAY DIFFRACTIONf_angle_d0.8709113424117384
X-RAY DIFFRACTIONf_chiral_restr0.0465447380179838
X-RAY DIFFRACTIONf_plane_restr0.005807288160671006
X-RAY DIFFRACTIONf_dihedral_angle_d21.44005182782040
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0007-2.03910.3371590253451480.2571939499482712X-RAY DIFFRACTION98.6887508627
2.0391-2.08070.3365445787121240.2410371467932730X-RAY DIFFRACTION99.5118549512
2.0807-2.12590.2768948983981460.2373811505662720X-RAY DIFFRACTION98.8275862069
2.1259-2.17540.2778639894411540.221330775412707X-RAY DIFFRACTION98.3837689133
2.1754-2.22970.278098861691360.2242459601972746X-RAY DIFFRACTION100
2.2297-2.290.2677327500811210.2177404980932727X-RAY DIFFRACTION98.4785615491
2.29-2.35730.2709047432541370.2134333974862763X-RAY DIFFRACTION98.6730180333
2.3573-2.43330.2536368962341490.2066658685912733X-RAY DIFFRACTION99.3793103448
2.4333-2.52020.2708080903641350.2117912502072730X-RAY DIFFRACTION99.2723492723
2.5202-2.6210.285431951631550.209396412852739X-RAY DIFFRACTION99.0417522245
2.621-2.74010.2810608537141550.2084606609322723X-RAY DIFFRACTION99.1388219084
2.7401-2.88430.2871175013481360.2004880690712795X-RAY DIFFRACTION99.2549949204
2.8843-3.06470.2641180086431500.2023355089732758X-RAY DIFFRACTION99.3169398907
3.0647-3.30070.216210270671630.192661540472763X-RAY DIFFRACTION99.3885869565
3.3007-3.63180.2308309736111380.1800276997362808X-RAY DIFFRACTION99.7629529292
3.6318-4.15490.2035032978381300.1680210198942855X-RAY DIFFRACTION99.8327759197
4.1549-5.22550.1893646674091490.1573412937872845X-RAY DIFFRACTION99.6671105193
5.2255-23.6840.2128659620261370.1750607105952994X-RAY DIFFRACTION99.3337563452

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