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- PDB-5se6: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c... -

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Basic information

Entry
Database: PDB / ID: 5se6
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(nc4c(c(n1)OCc2nc(cn2C)c3ccccc3)ncn4C)C, micromolar IC50=0.099277
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-IEB / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsJoseph, C. / Groebke-Zbinden, K. / 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
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
C: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
D: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,34916
Polymers157,6534
Non-polymers1,69612
Water11,043613
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8374
Polymers39,4131
Non-polymers4243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8374
Polymers39,4131
Non-polymers4243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8374
Polymers39,4131
Non-polymers4243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8374
Polymers39,4131
Non-polymers4243
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)134.828, 134.828, 234.402
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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


Mass: 39413.203 Da / Num. of mol.: 4
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.: 4 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-IEB / 2,9-dimethyl-6-[(1-methyl-4-phenyl-1H-imidazol-2-yl)methoxy]-9H-purine


Mass: 334.375 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H18N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 613 / 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: 2.6 Å3/Da / Density % sol: 52.71 %
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: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 1, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→43.5 Å / Num. obs: 115791 / % possible obs: 99.9 % / Redundancy: 5.196 % / Biso Wilson estimate: 41.796 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.068 / Rrim(I) all: 0.076 / Χ2: 0.849 / Net I/σ(I): 16.3 / Num. measured all: 601686 / Scaling rejects: 121
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
1.95-25.0791.3971.1943575859785800.4721.55999.8
2-2.065.3260.9671.7644409834183380.641.074100
2.06-2.125.2740.7672.2342998816081530.7360.85299.9
2.12-2.185.2620.553.0941566790279000.8470.612100
2.18-2.255.1160.4493.8539143765476510.8890.5100
2.25-2.334.9410.3384.7836413737873700.9280.37899.9
2.33-2.425.0580.2666.1135961711771100.9560.29799.9
2.42-2.525.3870.2227.4736845684268400.9690.246100
2.52-2.635.3650.1629.9835526662266220.9830.18100
2.63-2.765.3070.13212.3333483631263090.9880.146100
2.76-2.915.2220.10215.3231185597459720.9940.113100
2.91-3.084.9260.0819.0127756563756350.9950.09100
3.08-3.35.3310.05726.3628422533353310.9980.063100
3.3-3.565.3950.04135.8326948499649950.9990.045100
3.56-3.95.2450.03343.323547448944890.9990.037100
3.9-4.364.8660.02849.0820249416441610.9990.03299.9
4.36-5.035.0930.02455.1418416361836160.9990.02699.9
5.03-6.175.4340.02454.5416699307530730.9990.02799.9
6.17-8.724.9650.02158.64117232363236110.02399.9
8.72-43.55.3090.01773.6268221295128510.01999.2

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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: 1.95→43.5 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.951 / SU B: 4.544 / SU ML: 0.119 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.15 / ESU R Free: 0.142 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: also consider alternative conformation of ligand in molecule 3
RfactorNum. reflection% reflectionSelection details
Rfree0.2193 5562 5 %RANDOM
Rwork0.177 ---
obs0.1791 105690 96.02 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 119.91 Å2 / Biso mean: 37.397 Å2 / Biso min: 19.76 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å2-0.19 Å20 Å2
2---0.39 Å20 Å2
3---1.26 Å2
Refinement stepCycle: final / Resolution: 1.95→43.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 133 613 10898
Biso mean--49.1 39.76 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01310580
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179674
X-RAY DIFFRACTIONr_angle_refined_deg1.8191.6614333
X-RAY DIFFRACTIONr_angle_other_deg1.4861.58122468
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.85451255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.40522.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.702151856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4261560
X-RAY DIFFRACTIONr_chiral_restr0.0920.21348
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211636
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022250
X-RAY DIFFRACTIONr_mcbond_it3.5763.7355008
X-RAY DIFFRACTIONr_mcbond_other3.5713.7345006
X-RAY DIFFRACTIONr_mcangle_it4.5115.5846255
LS refinement shellResolution: 1.95→2.001 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 384 -
Rwork0.353 7166 -
all-7550 -
obs--88.01 %

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