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

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Basic information

Entry
Database: PDB / ID: 5skg
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c2(cc1nc(nn1cc2)c3ccccc3)NC(=O)c4cc(nc(c4)NC5CC5)Cl, micromolar IC50=0.0061215
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-KFI / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 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)159,63116
Polymers157,6534
Non-polymers1,97812
Water11,007611
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9084
Polymers39,4131
Non-polymers4953
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)39,9084
Polymers39,4131
Non-polymers4953
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)39,9084
Polymers39,4131
Non-polymers4953
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)39,9084
Polymers39,4131
Non-polymers4953
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.253, 135.253, 234.974
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-KFI / 2-chloro-6-(cyclopropylamino)-N-[(4S)-2-phenyl[1,2,4]triazolo[1,5-a]pyridin-7-yl]pyridine-4-carboxamide


Mass: 404.852 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H17ClN6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 611 / 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: 2.62 Å3/Da / Density % sol: 53.12 %
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: Jul 16, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.03→43.51 Å / Num. obs: 103526 / % possible obs: 99.9 % / Redundancy: 5.203 % / Biso Wilson estimate: 43.403 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.067 / Rrim(I) all: 0.075 / Χ2: 0.855 / Net I/σ(I): 17.45 / Num. measured all: 538689 / Scaling rejects: 92
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
2.03-2.084.8761.2411.3137607772177130.5291.39299.9
2.08-2.145.0360.9531.6837304741374080.6541.06599.9
2.14-2.25.3790.6072.6638979725372460.8110.67399.9
2.2-2.275.2820.5443.0437289707070600.8390.60499.9
2.27-2.345.2950.4093.9536185683868340.9060.45499.9
2.34-2.435.2420.3174.9534781663866350.9420.353100
2.43-2.524.9910.2695.7131965640864050.9520.301100
2.52-2.625.1040.1987.7531085609060900.9730.221100
2.62-2.745.3910.1581031786589858960.9830.175100
2.74-2.875.4010.12412.4230382562756250.9910.137100
2.87-3.035.3450.09416.0528591535353490.9940.10499.9
3.03-3.215.1360.07120.7426069507750760.9960.079100
3.21-3.434.9740.05128.1923615475047480.9980.057100
3.43-3.715.4480.03739.2624133443144300.9990.041100
3.71-4.065.3370.0347.421732407240720.9990.033100
4.06-4.545.20.02554.5819117367836760.9990.02899.9
4.54-5.244.8880.02357.0115802323432330.9990.026100
5.24-6.425.5160.02357.27152082758275710.025100
6.42-9.085.1050.01965.77108422125212410.021100
9.08-43.515.4110.01683.4862171159114910.01799.1

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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: 2.03→43.51 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.246 / SU ML: 0.131 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.179 / ESU R Free: 0.158 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: ligand not well soluble, not 100% occupied, despite 2 days soaking; ligand pose clear but treat details of conformation with care;
RfactorNum. reflection% reflectionSelection details
Rfree0.2218 4938 5 %RANDOM
Rwork0.1835 ---
obs0.1853 94245 95.74 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 103.02 Å2 / Biso mean: 38.753 Å2 / Biso min: 19.96 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å2-0.23 Å20 Å2
2---0.45 Å20 Å2
3---1.47 Å2
Refinement stepCycle: final / Resolution: 2.03→43.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 124 611 10887
Biso mean--66.31 41.5 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01310572
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179652
X-RAY DIFFRACTIONr_angle_refined_deg1.3351.65914321
X-RAY DIFFRACTIONr_angle_other_deg1.2931.57822431
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.40351255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.11922.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.592151856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.151560
X-RAY DIFFRACTIONr_chiral_restr0.0660.21352
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211629
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022259
X-RAY DIFFRACTIONr_mcbond_it2.2323.9465008
X-RAY DIFFRACTIONr_mcbond_other2.2313.9455006
X-RAY DIFFRACTIONr_mcangle_it3.1975.9076255
LS refinement shellResolution: 2.03→2.083 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 325 -
Rwork0.363 6373 -
all-6698 -
obs--86.95 %

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