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- PDB-5dh4: PDE10 complexed with 5-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl... -

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Basic information

Entry
Database: PDB / ID: 5dh4
TitlePDE10 complexed with 5-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / 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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP 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-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
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-4PX / Chem-5AV / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 Å
AuthorsYan, Y.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.
Authors: Raheem, I.T. / Schreier, J.D. / Fuerst, J. / Gantert, L. / Hostetler, E.D. / Huszar, S. / Joshi, A. / Kandebo, M. / Kim, S.H. / Li, J. / Ma, B. / McGaughey, G. / Sharma, S. / Shipe, W.D. / ...Authors: Raheem, I.T. / Schreier, J.D. / Fuerst, J. / Gantert, L. / Hostetler, E.D. / Huszar, S. / Joshi, A. / Kandebo, M. / Kim, S.H. / Li, J. / Ma, B. / McGaughey, G. / Sharma, S. / Shipe, W.D. / Uslaner, J. / Vandeveer, G.H. / Yan, Y. / Renger, J.J. / Smith, S.M. / Coleman, P.J. / Cox, C.D.
History
DepositionAug 29, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 27, 2016Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,3309
Polymers79,2132
Non-polymers1,1177
Water1,49583
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,3405
Polymers39,6061
Non-polymers7344
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9904
Polymers39,6061
Non-polymers3833
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.600, 81.200, 155.820
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 39606.430 Da / Num. of mol.: 2 / Fragment: catalytic domain residues 439-779
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 5 types, 90 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-5AV / 5-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine


Mass: 293.775 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H12ClN5S
#5: Chemical ChemComp-4PX / 3-(1-hydroxy-2-methylpropan-2-yl)-5-phenyl-3,5-dihydro-1H-imidazo[4,5-c][1,8]naphthyridine-2,4-dione


Mass: 350.371 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H18N4O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O

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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: 1.98 Å3/Da / Density % sol: 37.9 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 100mM HEPES pH 7.0, 20% PEG3350, 200mM MgCl2, and 10mM 2-Mercaptoethanol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 17, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionRedundancy: 6.2 % / Number: 192423 / Rmerge(I) obs: 0.06 / Χ2: 1.03 / D res high: 2.2 Å / D res low: 50 Å / Num. obs: 30865 / % possible obs: 94.3
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
4.745010.0350.8566.6
3.764.7410.0470.8576.5
3.293.7610.0561.0266.2
2.993.2910.0751.3066.1
2.772.9910.111.2546.1
2.612.7710.1621.1086.1
2.482.6110.221.0116.1
2.372.4810.3340.986.2
2.282.3710.4320.9616.3
2.22.2810.5550.9546.1
ReflectionResolution: 2.2→50 Å / Num. obs: 30865 / % possible obs: 94.3 % / Redundancy: 6.2 % / Biso Wilson estimate: 44.43 Å2 / Rmerge(I) obs: 0.06 / Χ2: 1.029 / Net I/av σ(I): 24.398 / Net I/σ(I): 17.1 / Num. measured all: 192423
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
2.2-2.286.10.55526560.95482.9
2.28-2.376.30.43228220.96187
2.37-2.486.20.33429130.9890.9
2.48-2.616.10.2230661.01194.8
2.61-2.776.10.16231021.10896.1
2.77-2.996.10.1131491.25497.1
2.99-3.296.10.07532181.30698
3.29-3.766.20.05632331.02698.8
3.76-4.746.50.04732700.85798.3
4.74-506.60.03534360.85697.9

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
BUSTER-TNT2.11.5refinement
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.2→43.75 Å / Cor.coef. Fo:Fc: 0.9277 / Cor.coef. Fo:Fc free: 0.9173 / SU R Cruickshank DPI: 0.336 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.338 / SU Rfree Blow DPI: 0.219 / SU Rfree Cruickshank DPI: 0.221
RfactorNum. reflection% reflectionSelection details
Rfree0.2325 1554 5.04 %RANDOM
Rwork0.2032 ---
obs0.2102 30808 93.92 %-
Displacement parametersBiso max: 137.98 Å2 / Biso mean: 57.67 Å2 / Biso min: 23.13 Å2
Baniso -1Baniso -2Baniso -3
1--15.2409 Å20 Å20 Å2
2--15.9213 Å20 Å2
3----0.6804 Å2
Refine analyzeLuzzati coordinate error obs: 0.329 Å
Refinement stepCycle: final / Resolution: 2.2→43.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5041 0 68 83 5192
Biso mean--42.06 44 -
Num. residues----629
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1792SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes123HARMONIC8
X-RAY DIFFRACTIONt_gen_planes772HARMONIC8
X-RAY DIFFRACTIONt_it5244HARMONIC20
X-RAY DIFFRACTIONt_nbd1SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion680SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact6446SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5244HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7123HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion1.91
X-RAY DIFFRACTIONt_other_torsion18.47
LS refinement shellResolution: 2.2→2.28 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2585 127 5.07 %
Rwork0.2423 2378 -
all0.2432 2505 -
obs--93.92 %

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