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

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Basic information

Entry
Database: PDB / ID: 5sek
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1ccc2c(c1)nc(c(n2)C)CCc3nc(cn3C)c4ccccc4, micromolar IC50=0.005172
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-IFY / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 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)159,32516
Polymers157,6534
Non-polymers1,67212
Water10,701594
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8314
Polymers39,4131
Non-polymers4183
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)39,8314
Polymers39,4131
Non-polymers4183
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)39,8314
Polymers39,4131
Non-polymers4183
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)39,8314
Polymers39,4131
Non-polymers4183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.629, 135.629, 236.677
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-IFY / 2-methyl-3-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl]quinoxaline


Mass: 328.410 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H20N4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 594 / 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: 2.66 Å3/Da / Density % sol: 53.71 %
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: 0.9999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 17, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.624
11K, H, -L20.376
ReflectionResolution: 2.15→43.63 Å / Num. obs: 88274 / % possible obs: 100 % / Redundancy: 5.244 % / Biso Wilson estimate: 46.346 Å2 / CC1/2: 0.989 / Rmerge(I) obs: 0.152 / Rrim(I) all: 0.17 / Χ2: 0.856 / Net I/σ(I): 6.9 / Num. measured all: 462869 / Scaling rejects: 2
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
2.15-2.215.4331.161.4335426652065210.3981.284100
2.21-2.275.3891.0241.6834341637563730.4461.135100
2.27-2.335.3720.7742.1533386621662150.6050.858100
2.33-2.45.3130.6342.6131822598959890.6710.704100
2.4-2.485.1850.5263.1130232583258310.7550.585100
2.48-2.575.0110.4323.6728168562156210.8030.483100
2.57-2.675.2640.3544.6628729545854580.8590.393100
2.67-2.785.4560.3025.5828635524952480.8930.334100
2.78-2.95.4010.2456.5327033500550050.9310.272100
2.9-3.045.3390.2037.925600479747950.9440.225100
3.04-3.215.1650.1679.1923640457745770.9560.187100
3.21-3.44.9020.13910.5321102430543050.9640.156100
3.4-3.635.3180.12312.4621582405840580.9720.137100
3.63-3.935.2740.1113.4219747374837440.9760.12399.9
3.93-4.35.1670.10613.9818055349734940.9780.11999.9
4.3-4.814.7780.10113.9114999314031390.9750.115100
4.81-5.555.0480.10314.314064278627860.9740.115100
5.55-6.85.2960.114.512324232723270.9780.112100
6.8-9.624.8590.09414.68727179817960.9790.10699.9
9.62-43.635.2990.0915.64525710019920.9870.199.1

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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: 2.15→43.63 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.945 / SU B: 2.699 / SU ML: 0.075 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.041 / ESU R Free: 0.033 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.1971 4356 5 %RANDOM
Rwork0.1635 ---
obs0.1652 82223 98.05 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 92.56 Å2 / Biso mean: 39.998 Å2 / Biso min: 21.87 Å2
Baniso -1Baniso -2Baniso -3
1-1.71 Å20 Å20 Å2
2--1.71 Å20 Å2
3----3.41 Å2
Refinement stepCycle: final / Resolution: 2.15→43.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 108 594 10854
Biso mean--34.56 42.04 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.01310552
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179584
X-RAY DIFFRACTIONr_angle_refined_deg1.171.65614289
X-RAY DIFFRACTIONr_angle_other_deg1.1811.56922283
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.32851255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.55322.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.729151856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8441560
X-RAY DIFFRACTIONr_chiral_restr0.0550.21348
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211621
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022215
X-RAY DIFFRACTIONr_mcbond_it1.7214.2335008
X-RAY DIFFRACTIONr_mcbond_other1.7214.2325006
X-RAY DIFFRACTIONr_mcangle_it2.5756.3436255
LS refinement shellResolution: 2.15→2.206 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 314 -
Rwork0.293 5768 -
all-6082 -
obs--93.57 %

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