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- PDB-5sgn: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH n... -

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Basic information

Entry
Database: PDB / ID: 5sgn
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH n1(nc(nc1CCc3nn2c(nc(c2C)C)c(c3)C(F)(F)F)N4CCCC4)C, micromolar IC50=0.164550
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-IY6 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / Groebke-Zbinden, K. / 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
Revision 1.2Oct 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)159,58516
Polymers157,6534
Non-polymers1,93212
Water7,981443
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8964
Polymers39,4131
Non-polymers4833
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)39,8964
Polymers39,4131
Non-polymers4833
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)39,8964
Polymers39,4131
Non-polymers4833
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)39,8964
Polymers39,4131
Non-polymers4833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.420, 135.420, 235.183
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-IY6 / (4S)-2,3-dimethyl-6-{2-[1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl]ethyl}-7-(trifluoromethyl)imidazo[1,2-b]pyridazine


Mass: 393.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H22F3N7 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 443 / 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: 2.63 Å3/Da / Density % sol: 53.28 %
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: 1.00004 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 2.07→43.56 Å / Num. obs: 97978 / % possible obs: 100 % / Redundancy: 5.179 % / Biso Wilson estimate: 45.242 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.078 / Rrim(I) all: 0.087 / Χ2: 0.852 / Net I/σ(I): 14.94 / Num. measured all: 507471 / Scaling rejects: 45
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
2.07-2.124.9391.4381.2135898727472690.4271.61199.9
2.12-2.184.9760.9931.7535181707570700.6351.11199.9
2.18-2.255.2730.7672.2936220687368690.7380.85299.9
2.25-2.315.3480.6012.9135536664666450.820.667100
2.31-2.395.2920.4813.5834147645364520.8840.534100
2.39-2.475.2080.3854.3932750629462890.9150.42899.9
2.47-2.574.9620.35.4130069606260600.940.336100
2.57-2.675.0010.2376.9328759575457510.960.26599.9
2.67-2.795.3680.1958.6630031559555940.9770.216100
2.79-2.935.3770.14811.0228612532353210.9870.164100
2.93-3.095.3330.11514.0127133509150880.9910.12899.9
3.09-3.275.1550.08318.724541476147610.9950.093100
3.27-3.54.950.05725.4422333451445120.9970.064100
3.5-3.785.4070.04433.6522576417641750.9980.049100
3.78-4.145.3510.03540.8520676386438640.9990.039100
4.14-4.635.1630.0345.4818116351035090.9990.034100
4.63-5.344.8290.02846.1114676304030390.9990.032100
5.34-6.555.4650.03145.8614263261026100.9990.034100
6.55-9.265.0490.02254.99101742016201510.024100
9.26-43.565.3270.01767.7857801094108510.01999.2

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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: 2.07→43.56 Å / Cor.coef. Fo:Fc: 0.969 / Cor.coef. Fo:Fc free: 0.95 / SU B: 5.547 / SU ML: 0.137 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.176 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: trifluoromethyl group is shifted by one carbon to ortho-position; close contacts between fluorine and Phe696 and Met713;
RfactorNum. reflection% reflectionSelection details
Rfree0.2221 4696 5 %RANDOM
Rwork0.1721 ---
obs0.1745 89750 96.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 132.02 Å2 / Biso mean: 40.469 Å2 / Biso min: 20.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.48 Å2-0.24 Å2-0 Å2
2---0.48 Å2-0 Å2
3---1.57 Å2
Refinement stepCycle: final / Resolution: 2.07→43.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10171 0 120 443 10734
Biso mean--38.49 40.72 -
Num. residues----1254
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.01310603
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179605
X-RAY DIFFRACTIONr_angle_refined_deg2.0171.65914386
X-RAY DIFFRACTIONr_angle_other_deg1.5231.56922343
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.29251268
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90822.491554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.766151860
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1071559
X-RAY DIFFRACTIONr_chiral_restr0.1080.21364
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.0211675
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022218
X-RAY DIFFRACTIONr_mcbond_it4.274.0915030
X-RAY DIFFRACTIONr_mcbond_other4.2664.0895028
X-RAY DIFFRACTIONr_mcangle_it5.2196.1116285
LS refinement shellResolution: 2.07→2.124 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.403 321 -
Rwork0.338 6165 -
all-6486 -
obs--89.34 %

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