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- PDB-7vtx: Crystal structure of PDE8A catalytic domain in complex with 22 -

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Basic information

Entry
Database: PDB / ID: 7vtx
TitleCrystal structure of PDE8A catalytic domain in complex with 22
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-80D / 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: 2.50010936848 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

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Structure visualization

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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)39,5974
Polymers39,0901
Non-polymers5073
Water1,20767
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area240 Å2
ΔGint-49 kcal/mol
Surface area15550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.936, 132.005, 101.592
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-80D / 2-chloro-9-(3-(2,2-difluoroethoxy)-5-(pyridin-4-yl)benzyl)-9H-purin-6-amine


Mass: 416.812 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15ClF2N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / 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

CrystalDensity Matthews: 3.26 Å3/Da / Density % sol: 62.23 %
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: Nov 9, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5406 Å / Relative weight: 1
ReflectionResolution: 2.5→24.22 Å / Num. obs: 17373 / % possible obs: 96.1 % / Redundancy: 4.1 % / Biso Wilson estimate: 45.4803857948 Å2 / Rmerge(I) obs: 0.109 / Net I/σ(I): 17.23
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.387 / Num. unique obs: 1740

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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: 2.50010936848→24.2179376811 Å / SU ML: 0.344947110964 / Cross valid method: THROUGHOUT / σ(F): 1.96775493744 / Phase error: 27.5532404723
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.276666014121 877 5.05417242969 %
Rwork0.246173473109 16475 -
obs0.247760991845 17352 96.2502773464 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.323980344 Å2
Refinement stepCycle: LAST / Resolution: 2.50010936848→24.2179376811 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2740 0 31 67 2838
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.007872709838252850
X-RAY DIFFRACTIONf_angle_d1.123058554433872
X-RAY DIFFRACTIONf_chiral_restr0.0617041476617419
X-RAY DIFFRACTIONf_plane_restr0.00449272396822535
X-RAY DIFFRACTIONf_dihedral_angle_d17.51284400031069
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.50011-2.65660.3306139042571060.2852396739892850X-RAY DIFFRACTION99.9661819412
2.6566-2.86140.3296363680981650.2706969025992801X-RAY DIFFRACTION99.8653198653
2.8614-3.14880.2969225156731340.263126109752831X-RAY DIFFRACTION99.4966442953
3.1488-3.60310.2859659044021450.248402337562759X-RAY DIFFRACTION97.5478669802
3.6031-4.53470.2685992911091810.2316459211892654X-RAY DIFFRACTION93.9675174014
4.5347-5.250.2476765832661460.2353651890052580X-RAY DIFFRACTION87.232

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