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

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Basic information

Entry
Database: PDB / ID: 5sfn
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c12c(cccc1)n(C)c(n2)CCNC(c4c(C(=O)N3CCC3)cnn4C)=O, micromolar IC50=0.01602
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-ILS / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsJoseph, C. / Koerner, M. / 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)159,47716
Polymers157,6534
Non-polymers1,82512
Water8,791488
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8694
Polymers39,4131
Non-polymers4563
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)39,8694
Polymers39,4131
Non-polymers4563
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)39,8694
Polymers39,4131
Non-polymers4563
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)39,8694
Polymers39,4131
Non-polymers4563
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.677, 135.677, 235.330
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-ILS / 4-(azetidine-1-carbonyl)-1-methyl-N-[2-(1-methyl-1H-benzimidazol-2-yl)ethyl]-1H-pyrazole-5-carboxamide


Mass: 366.417 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H22N6O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 488 / 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: 2.64 Å3/Da / Density % sol: 53.48 %
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: Oct 17, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→43.64 Å / Num. obs: 105885 / % possible obs: 100 % / Redundancy: 5.187 % / Biso Wilson estimate: 46.595 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.073 / Rrim(I) all: 0.081 / Χ2: 0.847 / Net I/σ(I): 13.95 / Num. measured all: 549193 / Scaling rejects: 60
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
2.02-2.075.2331.4841.1240912782078180.4231.65100
2.07-2.135.1681.2071.3739601766876630.5281.34599.9
2.13-2.194.9370.8711.8936551741074030.6890.97599.9
2.19-2.265.10.6662.5137033726672620.7820.74399.9
2.26-2.335.380.5053.3137488697169680.8710.56100
2.33-2.415.3510.3974.1636082674567430.9140.441100
2.41-2.515.2620.3225.0734395653865360.9390.358100
2.51-2.615.1330.2446.6132202627462730.9620.272100
2.61-2.724.9550.198.2429678599159890.9730.213100
2.72-2.865.3390.14910.530831577557750.9860.165100
2.86-3.015.3630.11113.7929378548154780.9920.12399.9
3.01-3.195.2960.08517.5827335516451610.9950.09499.9
3.19-3.415.0210.06123.4724369485448530.9970.068100
3.41-3.695.0340.04630.8122903455245500.9980.051100
3.69-4.045.3640.03838.2322422418041800.9990.042100
4.04-4.525.230.03342.9619748377837760.9990.03699.9
4.52-5.224.8330.0344.0416064332633240.9990.03499.9
5.22-6.395.2980.02844.4614628276127610.9990.032100
6.39-9.035.2020.02250.1111393219021900.9990.025100
9.03-43.645.2280.01957.8261801191118210.02199.2

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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: 2.02→43.64 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.953 / SU B: 5.287 / SU ML: 0.133 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.166 / ESU R Free: 0.155 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2224 5078 5 %RANDOM
Rwork0.1778 ---
obs0.18 96629 96.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 119.96 Å2 / Biso mean: 42.172 Å2 / Biso min: 23.53 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å2-0.17 Å20 Å2
2---0.34 Å2-0 Å2
3---1.11 Å2
Refinement stepCycle: final / Resolution: 2.02→43.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 116 488 10756
Biso mean--52.55 42.88 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01310551
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179660
X-RAY DIFFRACTIONr_angle_refined_deg1.7971.65714292
X-RAY DIFFRACTIONr_angle_other_deg1.4531.58122452
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9351253
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.56322.464552
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.062151853
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7721559
X-RAY DIFFRACTIONr_chiral_restr0.0890.21347
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211608
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022229
X-RAY DIFFRACTIONr_mcbond_it3.9874.2615006
X-RAY DIFFRACTIONr_mcbond_other3.9834.265004
X-RAY DIFFRACTIONr_mcangle_it4.866.3696252
LS refinement shellResolution: 2.02→2.072 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.381 338 -
Rwork0.363 6619 -
all-6957 -
obs--89.1 %

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