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- PDB-5sdy: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c... -

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Basic information

Entry
Database: PDB / ID: 5sdy
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c4(c(NC(c1nc(ccc1Nc2cncnc2)C3CC3)=O)cnn4CCOC)C(N(C)C)=O, micromolar IC50=0.012613
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE inhibitor / PHOSPHODIESTERASE / PDE10 / HYDROLASE / SCHIZOPHRENIA / HYDROLASE-HYDROLASE inhibitor complex
Function / homology
Function and homology information


3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cGMP effects / cAMP catabolic process / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / G alpha (s) signalling events / 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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF 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. / GAF domain / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain
Similarity search - Domain/homology
Chem-IB4 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsJoseph, C. / Rodriguez-Sarmiento, R.M. / Benz, J. / Schlatter, D. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche Switzerland
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2022
Title: A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.
Authors: Tosstorff, A. / Rudolph, M.G. / Cole, J.C. / Reutlinger, M. / Kramer, C. / Schaffhauser, H. / Nilly, A. / Flohr, A. / Kuhn, B.
History
DepositionJan 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary
Category: pdbx_entry_details / pdbx_modification_feature / struct
Item: _pdbx_entry_details.has_protein_modification / _struct.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9534
Polymers39,4131
Non-polymers5403
Water3,711206
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, elutes as a monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)141.546, 141.546, 141.546
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number197
Space group name H-MI23

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Components

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 39413.203 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Plasmid: PET28a(+) / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide 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-IB4 / 6-cyclopropyl-N-[5-(dimethylcarbamoyl)-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-[(pyrimidin-5-yl)amino]pyridine-2-carboxamide


Mass: 450.494 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N8O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / 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 Å3/Da / Density % sol: 58.97 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 5-20 mg/mL protein in 25mM HEPES/NaOH pH7.5, 150mM NaCl, 50mM BME mixed 1:1 with reservoir 0.1M HEPES/NaOH pH7.5, 30% PEG550MME, 50mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9999 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Mar 2, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.2→44.76 Å / Num. obs: 23987 / % possible obs: 99.6 % / Redundancy: 5.378 % / Biso Wilson estimate: 45.998 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.084 / Rrim(I) all: 0.093 / Χ2: 0.86 / Net I/σ(I): 15.28 / Num. measured all: 129013 / Scaling rejects: 44
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.2-2.264.511.0481.477861175517430.5451.18699.3
2.26-2.324.6220.8561.837954173617210.6520.96799.1
2.32-2.394.7470.7662.197884167116610.6890.86499.4
2.39-2.464.8520.5922.767773161116020.7920.66699.4
2.46-2.544.9770.4643.527868158615810.8520.5299.7
2.54-2.635.1170.374.517737152115120.90.41499.4
2.63-2.735.1740.315.627771150815020.9250.34699.6
2.73-2.845.3490.2636.537392138413820.9560.29399.9
2.84-2.975.4390.1978.747429136913660.9690.21899.8
2.97-3.115.5870.15611.057230129612940.9810.17299.8
3.11-3.285.80.11714.757123123012280.9890.12999.8
3.28-3.485.9470.07921.057059118811870.9960.08799.9
3.48-3.726.1070.06426.286815111711160.9970.07199.9
3.72-4.026.1890.04933.86356102710270.9980.054100
4.02-4.46.1920.0439.0858709489480.9990.044100
4.4-4.926.1840.03345.8354058748740.9990.036100
4.92-5.686.1580.03144.2247487717710.9990.034100
5.68-6.966.1090.0343.5440386616610.9990.033100
6.96-9.845.9590.02258.42303951051010.024100
9.84-44.765.5180.0265.8116613093010.9990.02297.4

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.2→44.76 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.95 / SU B: 6.436 / SU ML: 0.15 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.218 / ESU R Free: 0.185 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: sidechain on pyrazole not well defined by electron density close contact of methyl group in dimethylamido moiety with Met side-chain
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1113 4.9 %RANDOM
Rwork0.1808 ---
obs0.1829 21414 93.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 108.11 Å2 / Biso mean: 38.963 Å2 / Biso min: 22.79 Å2
Refinement stepCycle: final / Resolution: 2.2→44.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2556 0 35 206 2797
Biso mean--57.07 43.22 -
Num. residues----315
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0132668
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172416
X-RAY DIFFRACTIONr_angle_refined_deg1.3461.6613613
X-RAY DIFFRACTIONr_angle_other_deg1.3071.5685618
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5185316
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.1622.446139
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.38715466
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8431515
X-RAY DIFFRACTIONr_chiral_restr0.0660.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022928
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02556
X-RAY DIFFRACTIONr_mcbond_it2.1763.9611261
X-RAY DIFFRACTIONr_mcbond_other2.1693.9581260
X-RAY DIFFRACTIONr_mcangle_it3.1515.9341575
LS refinement shellResolution: 2.2→2.257 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.411 57 -
Rwork0.318 1416 -
all-1473 -
obs--84.27 %

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