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- PDB-5se5: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c... -

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Basic information

Entry
Database: PDB / ID: 5se5
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c4ncc(Nc1ncc(nc1C(Nc2c(n(C)nc2)C(=O)NC)=O)C3CC3)cn4, micromolar IC50=0.0069268
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-IEH / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsJoseph, C. / Groebke-Zbinden, K. / Benz, J. / Schlatter, D. / Rudolph, M.G.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
F. Hoffmann-La Roche Switzerland
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2022
Title: A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.
Authors: Tosstorff, A. / Rudolph, M.G. / Cole, J.C. / Reutlinger, M. / Kramer, C. / Schaffhauser, H. / Nilly, A. / Flohr, A. / Kuhn, B.
History
DepositionJan 21, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 12, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 3, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 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
Water8,485471
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)134.910, 134.910, 234.914
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-IEH / 6-cyclopropyl-N-[1-methyl-5-(methylcarbamoyl)-1H-pyrazol-4-yl]-3-[(pyrimidin-5-yl)amino]pyrazine-2-carboxamide


Mass: 393.403 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H19N9O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 471 / 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: 2.61 Å3/Da / Density % sol: 52.87 %
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: Apr 23, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.08→43.4 Å / Num. obs: 95514 / % possible obs: 99.8 % / Redundancy: 4.356 % / Biso Wilson estimate: 46.763 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.069 / Rrim(I) all: 0.078 / Χ2: 0.853 / Net I/σ(I): 14 / Num. measured all: 416044 / Scaling rejects: 63
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
2.08-2.134.3711.1931.2530812705970490.4581.3699.9
2.13-2.194.3080.8491.7629444687268340.6030.97199.4
2.19-2.264.120.7182.0627762675467380.6710.82699.8
2.26-2.334.3050.5252.8127932650164880.7950.699.8
2.33-2.44.4990.4243.5328595636363560.8630.48299.9
2.4-2.494.4690.3544.2227125608160690.9040.40299.8
2.49-2.584.410.2695.4326011590758980.9370.30699.8
2.58-2.694.270.2017.0824314570556940.960.2399.8
2.69-2.84.1730.1648.422493540353900.9720.18999.8
2.8-2.944.5180.12910.8323510521752040.9860.14699.8
2.94-3.14.5050.09514.322309495749520.9910.10899.9
3.1-3.294.4470.0718.6920801469846780.9950.07999.6
3.29-3.524.2070.04924.9118289436043470.9970.05699.7
3.52-3.84.310.0430.8417791413341280.9980.04599.9
3.8-4.164.5590.03237.917102375537510.9990.03699.9
4.16-4.654.4540.02941.8115095339533890.9990.03399.8
4.65-5.374.130.02841.8812356299929920.9990.03399.8
5.37-6.584.4690.02941.7811391255025490.9990.033100
6.58-9.34.3480.02448.858440195219410.9990.02899.4
9.3-43.44.1910.02454.324472108110670.9990.02798.7

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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: 2.08→43.4 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.948 / SU B: 5.771 / SU ML: 0.142 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.196 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2259 4650 5 %RANDOM
Rwork0.1858 ---
obs0.1878 87788 96.55 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.25 Å2 / Biso mean: 42.853 Å2 / Biso min: 23.15 Å2
Baniso -1Baniso -2Baniso -3
1--0.16 Å2-0.08 Å20 Å2
2---0.16 Å20 Å2
3---0.51 Å2
Refinement stepCycle: final / Resolution: 2.08→43.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 124 471 10747
Biso mean--38.45 43.36 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.01310568
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179584
X-RAY DIFFRACTIONr_angle_refined_deg1.3731.65814313
X-RAY DIFFRACTIONr_angle_other_deg1.2941.56922283
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.68451255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.91722.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.888151856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8131560
X-RAY DIFFRACTIONr_chiral_restr0.0690.21352
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211661
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022215
X-RAY DIFFRACTIONr_mcbond_it2.6424.4015008
X-RAY DIFFRACTIONr_mcbond_other2.6354.45006
X-RAY DIFFRACTIONr_mcangle_it3.8366.5916255
LS refinement shellResolution: 2.08→2.134 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 319 -
Rwork0.352 6029 -
all-6348 -
obs--90.23 %

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