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- PDB-5shb: Crystal Structure of human phosphodiesterase 10 in complex with 3... -

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Basic information

Entry
Database: PDB / ID: 5shb
TitleCrystal Structure of human phosphodiesterase 10 in complex with 3-[2-(3-bromophenyl)pyrazol-3-yl]-1-pyridin-4-ylpyridazin-4-one
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


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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / G alpha (s) signalling events / signal transduction / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain ...3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / 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-JCJ / 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. / Benz, J. / Flohr, A. / Koerner, M. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche Switzerland
CitationJournal: To be published
Title: Crystal Structure of a human phosphodiesterase 10 complex
Authors: Flohr, A. / Schlatter, D. / Kuhn, B. / Rudolph, M.G.
History
DepositionFeb 1, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)159,58916
Polymers157,6534
Non-polymers1,93612
Water13,529751
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8974
Polymers39,4131
Non-polymers4843
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)39,8974
Polymers39,4131
Non-polymers4843
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)39,8974
Polymers39,4131
Non-polymers4843
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)39,8974
Polymers39,4131
Non-polymers4843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.358, 135.358, 235.610
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-JCJ / 3-[1-(3-bromophenyl)-1H-pyrazol-5-yl]-1-(pyridin-4-yl)pyridazin-4(1H)-one


Mass: 394.225 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H12BrN5O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 751 / 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: 2.63 Å3/Da / Density % sol: 53.32 %
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: MARMOSAIC 225 mm CCD / Detector: CCD / Date: May 25, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.95→43.72 Å / Num. obs: 115608 / % possible obs: 98.5 % / Redundancy: 3.854 % / Biso Wilson estimate: 38.847 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.063 / Rrim(I) all: 0.073 / Χ2: 0.893 / Net I/σ(I): 13.89 / Num. measured all: 445565 / Scaling rejects: 67
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
1.95-23.5730.9071.4127851866777940.5471.05889.9
2-2.063.8810.6572.0932479849783690.6870.76198.5
2.06-2.123.8780.532.5931407820380980.7740.61498.7
2.12-2.183.8860.3873.530624797678810.8680.44898.8
2.18-2.253.8730.3144.3929822778376990.9080.36498.9
2.25-2.333.8880.2515.4128839748774180.9430.29199.1
2.33-2.423.8970.2026.5727805719471350.9610.23499.2
2.42-2.523.8990.1687.8527093699969480.9720.19499.3
2.52-2.633.8980.12610.2525785665466150.9830.14699.4
2.63-2.763.8980.10312.3224792639263610.9880.1299.5
2.76-2.913.8990.08514.6323420603860060.9930.09899.5
2.91-3.083.8940.06918.0522383576857480.9950.07999.7
3.08-3.33.8830.05422.7720794537653550.9960.06299.6
3.3-3.563.8440.0429.0719297503450200.9980.04799.7
3.56-3.93.8010.03533.6517391458945750.9980.04199.7
3.9-4.363.8040.0337.7915850417341670.9990.03599.9
4.36-5.033.8150.02740.9314098370036950.9990.03299.9
5.03-6.173.8650.02739.8611989310431020.9990.03199.9
6.17-8.723.8810.02143.199260239023860.9990.02499.8
8.72-43.723.710.01747.244586131412360.9990.0294.1

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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→43.72 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.951 / SU B: 4.087 / SU ML: 0.109 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.154 / ESU R Free: 0.14 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: ligand well defined, bromine atom with some negative difference density: may be partially radiolyzed by xrays;
RfactorNum. reflection% reflectionSelection details
Rfree0.2149 5592 5 %RANDOM
Rwork0.1805 ---
obs0.1822 106296 95.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.71 Å2 / Biso mean: 34.323 Å2 / Biso min: 17.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å2-0.04 Å20 Å2
2---0.08 Å20 Å2
3---0.26 Å2
Refinement stepCycle: final / Resolution: 1.95→43.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 108 751 11011
Biso mean--33.62 39.86 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.01310590
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179623
X-RAY DIFFRACTIONr_angle_refined_deg1.2541.65614350
X-RAY DIFFRACTIONr_angle_other_deg1.2831.56922382
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.30751269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.97322.33558
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.91151867
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1361562
X-RAY DIFFRACTIONr_chiral_restr0.0670.21355
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211686
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022232
X-RAY DIFFRACTIONr_mcbond_it1.7523.5125022
X-RAY DIFFRACTIONr_mcbond_other1.753.5115020
X-RAY DIFFRACTIONr_mcangle_it2.5645.2576276
LS refinement shellResolution: 1.95→2.001 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.382 361 -
Rwork0.325 6586 -
all-6947 -
obs--80.32 %

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