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

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Basic information

Entry
Database: PDB / ID: 5skc
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(c(ccc(n1)C)Nc2cncnc2)C(Nc3nn(cc3)C(C)C)=O, micromolar IC50=0.204685
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE inhibitor / PHOSPHODIESTERASE / PDE10 / HYDROLASE / 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-KE6 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / Vieira, E. / 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)159,36116
Polymers157,6534
Non-polymers1,70812
Water2,270126
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8404
Polymers39,4131
Non-polymers4273
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)39,8404
Polymers39,4131
Non-polymers4273
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)39,8404
Polymers39,4131
Non-polymers4273
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)39,8404
Polymers39,4131
Non-polymers4273
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)136.690, 136.690, 236.140
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-KE6 / 6-methyl-N-[1-(propan-2-yl)-1H-pyrazol-3-yl]-3-[(pyrimidin-5-yl)amino]pyridine-2-carboxamide


Mass: 337.379 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H19N7O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / 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: 2.69 Å3/Da / Density % sol: 54.33 %
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: Sep 15, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.59→43.87 Å / Num. obs: 50904 / % possible obs: 99.5 % / Redundancy: 4.867 % / Biso Wilson estimate: 69.79 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.111 / Rrim(I) all: 0.125 / Χ2: 0.83 / Net I/σ(I): 10.08 / Num. measured all: 247733 / Scaling rejects: 125
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
2.59-2.664.8752.730.6217902376936720.1913.06697.4
2.66-2.734.8441.9540.917637367536410.3062.19599.1
2.73-2.814.871.6611.0917368357835660.3651.86599.7
2.81-2.94.8851.2641.4316873346634540.5211.41799.7
2.9-2.994.8850.9421.9116643341334070.6521.05699.8
2.99-3.14.8890.6962.6616149330533030.7790.7899.9
3.1-3.214.8910.5113.5815129309630930.8670.57299.9
3.21-3.344.9080.3555.0315014306130590.9310.39799.9
3.34-3.494.8620.2447.2414006289028810.9630.27399.7
3.49-3.664.8790.1899.0713555278127780.9760.21199.9
3.66-3.864.7630.13212.5412588265026430.9840.14999.7
3.86-4.14.780.09815.7811907250424910.9910.1199.5
4.1-4.384.9010.07119.7311523235523510.9950.0899.8
4.38-4.734.8760.05623.6110556216921650.9970.06399.8
4.73-5.184.8760.05325.29928203620360.9970.06100
5.18-5.794.9060.05125.348830180318000.9980.05799.8
5.79-6.694.8960.05226.047888161116110.9980.058100
6.69-8.194.90.03831.856679136513630.9980.04299.9
8.19-11.584.8350.0336.724980103510300.9990.03499.5
11.58-43.874.6040.0337.0325785865600.9990.03495.6

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
REFMAC5.8.0258refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.6→43.87 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.943 / SU R Cruickshank DPI: 0.613 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.527 / SU Rfree Blow DPI: 0.274 / SU Rfree Cruickshank DPI: 0.286
Details: ligand in molecule D not well defined. some water molecules at metal clusters with excessive B-values. Structure refined with -autoncs and -target
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 2468 4.9 %RANDOM
Rwork0.2161 ---
obs0.2174 50361 99.6 %-
Solvent computationSolvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 146.96 Å2 / Biso mean: 73.43 Å2 / Biso min: 37.77 Å2
Baniso -1Baniso -2Baniso -3
1--0.2942 Å20 Å20 Å2
2---0.2942 Å20 Å2
3---0.5885 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: final / Resolution: 2.6→43.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10170 0 108 126 10404
Biso mean--73.53 55.22 -
Num. residues----1254
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3681SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1763HARMONIC5
X-RAY DIFFRACTIONt_it10546HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1348SEMIHARMONIC5
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_contact8401SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d10546HARMONIC20.009
X-RAY DIFFRACTIONt_angle_deg14275HARMONIC20.89
X-RAY DIFFRACTIONt_omega_torsion2.81
X-RAY DIFFRACTIONt_other_torsion19.8
LS refinement shellResolution: 2.6→2.62 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.5387 51 5.06 %
Rwork0.4349 957 -
all0.4397 1008 -
obs--94.85 %

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