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- PDB-7vtw: Crystal structure of PDE8A catalytic domain in complex with 17 -

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Basic information

Entry
Database: PDB / ID: 7vtw
TitleCrystal structure of PDE8A catalytic domain in complex with 17
ComponentsHigh affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A
KeywordsHYDROLASE / cAMP-specific / Selective PDE8A inhibitor
Function / homology
Function and homology information


3',5'-cyclic-AMP phosphodiesterase / protein kinase activator activity / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to epidermal growth factor stimulus / cAMP-mediated signaling / kinase binding / G alpha (s) signalling events / positive regulation of ERK1 and ERK2 cascade ...3',5'-cyclic-AMP phosphodiesterase / protein kinase activator activity / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cellular response to epidermal growth factor stimulus / cAMP-mediated signaling / kinase binding / G alpha (s) signalling events / positive regulation of ERK1 and ERK2 cascade / regulation of DNA-templated transcription / perinuclear region of cytoplasm / extracellular exosome / nucleus / metal ion binding / cytosol
Similarity search - Function
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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / PAS fold ...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. / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / PAS fold / PAS fold / PAS repeat profile. / PAS domain / PAS domain superfamily
Similarity search - Domain/homology
Chem-807 / High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.79971328057 Å
AuthorsWu, X.-N. / Zhou, Q. / Huang, Y.-D. / Li, Z. / Wu, Y. / Luo, H.-B.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21877134 China
National Natural Science Foundation of China (NSFC)22077143 China
CitationJournal: To Be Published
Title: Structure-Based Discovery of Orally Efficient PDE8 Inhibitors for the Treatment of Vascular Dementia
Authors: Wu, X.-N. / Zhou, Q. / Huang, Y.-D. / Li, Z. / Wu, Y. / Luo, H.-B.
History
DepositionOct 31, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,5784
Polymers39,0901
Non-polymers4883
Water66737
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-49 kcal/mol
Surface area15230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.851, 131.750, 101.358
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2

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Components

#1: Protein High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A


Mass: 39090.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE8A / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: O60658, 3',5'-cyclic-AMP phosphodiesterase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-807 / 2-chloro-9-(3-(2,2-difluoroethoxy)-5-isopropoxybenzyl)-9H-purin-6-amine


Mass: 397.807 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H18ClF2N5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 3.24 Å3/Da / Density % sol: 62.03 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 100mM Cacodylate Sodium pH 6.5, 15% Isopropanol, 30% Ethylene Glycol, 11% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SEALED TUBE / Type: OXFORD DIFFRACTION NOVA / Wavelength: 1.5406 Å
DetectorType: OXFORD ONYX CCD / Detector: CCD / Date: Jul 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5406 Å / Relative weight: 1
ReflectionResolution: 2.799→24.173 Å / Num. obs: 12812 / % possible obs: 99.5 % / Redundancy: 5.2 % / Biso Wilson estimate: 45.9311676557 Å2 / Rmerge(I) obs: 0.103 / Net I/σ(I): 18.73
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.276 / Num. unique obs: 1283

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Processing

Software
NameVersionClassification
PHENIX1.10_2155refinement
REFMAC6.5.0refinement
CrysalisPro38.41data reduction
CrysalisPro38.41data scaling
MOLREP6.5.0phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ECM

3ecm


Resolution: 2.79971328057→24.1726451871 Å / SU ML: 0.420550145062 / Cross valid method: THROUGHOUT / σ(F): 1.96981342147 / Phase error: 29.0159321752
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.306544390431 677 5.28823621309 %
Rwork0.269541640617 12125 -
obs0.271468360447 12802 99.7662094763 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.2347383513 Å2
Refinement stepCycle: LAST / Resolution: 2.79971328057→24.1726451871 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2713 0 29 37 2779
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007266188060322820
X-RAY DIFFRACTIONf_angle_d1.090842894333836
X-RAY DIFFRACTIONf_chiral_restr0.0533318316894419
X-RAY DIFFRACTIONf_plane_restr0.00468260999075523
X-RAY DIFFRACTIONf_dihedral_angle_d17.04406054341042
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-3.01550.3560252234061380.3115555111632378X-RAY DIFFRACTION99.6435643564
3.0155-3.31830.301867158481320.2896398718872405X-RAY DIFFRACTION99.9212288302
3.3183-3.79680.320493452541080.2633590020922430X-RAY DIFFRACTION100
3.7968-4.77760.2970698057621710.2546845215132387X-RAY DIFFRACTION99.921875
4.7776-6.130.2920946495221280.264729850572525X-RAY DIFFRACTION99.3632958801

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