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- PDB-7cwa: Crystal structure of PDE8A catalytic domain in complex with clofa... -

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Basic information

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


3',5'-cyclic-AMP phosphodiesterase / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / protein kinase activator activity / : / cellular response to epidermal growth factor stimulus / kinase binding / G alpha (s) signalling events / positive regulation of ERK1 and ERK2 cascade ...3',5'-cyclic-AMP phosphodiesterase / cAMP catabolic process / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / protein kinase activator activity / : / cellular response to epidermal growth factor stimulus / kinase binding / G alpha (s) signalling events / positive regulation of ERK1 and ERK2 cascade / regulation of DNA-templated transcription / extracellular exosome / metal ion binding / cytosol
Similarity search - Function
PDE8A-like, N-terminal domain / 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 ...PDE8A-like, N-terminal domain / 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-CFB / 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: 2.8 Å
AuthorsHuang, Y. / Wu, X.-N. / Zhou, Q. / 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)81522041 China
CitationJournal: J.Med.Chem. / Year: 2020
Title: Rational Design of 2-Chloroadenine Derivatives as Highly Selective Phosphodiesterase 8A Inhibitors.
Authors: Huang, Y. / Wu, X.N. / Zhou, Q. / Wu, Y. / Zheng, D. / Li, Z. / Guo, L. / Luo, H.B.
History
DepositionAug 27, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 6, 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:
MolmilJmol/JSmol

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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)39,4834
Polymers39,0901
Non-polymers3933
Water79344
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area90 Å2
ΔGint-30 kcal/mol
Surface area15740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.261, 132.246, 101.916
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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) / Strain (production host): BL21
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
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CFB / 2-CHLORO-9-(2-DEOXY-2-FLUORO-B -D-ARABINOFURANOSYL)-9H-PURIN-6-AMINE / CLOFARABINE


Mass: 303.677 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H11ClFN5O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / 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: 3.38 Å3/Da / Density % sol: 63.62 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 100 mM 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 30, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5406 Å / Relative weight: 1
ReflectionResolution: 2.8→24.26 Å / Num. obs: 13022 / % possible obs: 99.7 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.096 / Net I/σ(I): 15.84
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.276 / Mean I/σ(I) obs: 4.12 / Num. unique obs: 1304 / % possible all: 100

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Processing

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

3ecn


Resolution: 2.8→24.26 Å / Cor.coef. Fo:Fc: 0.809 / Cor.coef. Fo:Fc free: 0.71 / SU B: 23.763 / SU ML: 0.474 / Cross valid method: THROUGHOUT / ESU R: 4.315 / ESU R Free: 0.487 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.33298 571 4.8 %RANDOM
Rwork0.28872 ---
obs0.2909 11260 90.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.493 Å2
Baniso -1Baniso -2Baniso -3
1--2.95 Å20 Å2-0 Å2
2---1.95 Å20 Å2
3---4.9 Å2
Refinement stepCycle: 1 / Resolution: 2.8→24.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2721 0 22 44 2787
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192809
X-RAY DIFFRACTIONr_bond_other_d0.0010.022565
X-RAY DIFFRACTIONr_angle_refined_deg0.9141.9343821
X-RAY DIFFRACTIONr_angle_other_deg0.84935901
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.695337
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.81524.653144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.82315465
X-RAY DIFFRACTIONr_dihedral_angle_4_deg9.5521515
X-RAY DIFFRACTIONr_chiral_restr0.0470.2422
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0213256
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02665
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5163.8411351
X-RAY DIFFRACTIONr_mcbond_other0.5163.8381350
X-RAY DIFFRACTIONr_mcangle_it0.9715.7561687
X-RAY DIFFRACTIONr_mcangle_other0.9715.761688
X-RAY DIFFRACTIONr_scbond_it0.2153.81458
X-RAY DIFFRACTIONr_scbond_other0.2153.7991459
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other0.475.6952135
X-RAY DIFFRACTIONr_long_range_B_refined2.59329.8783251
X-RAY DIFFRACTIONr_long_range_B_other2.53729.8663243
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.87 Å
RfactorNum. reflection% reflection
Rfree0.425 29 -
Rwork0.341 853 -
obs--91.21 %

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