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

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Basic information

Entry
Database: PDB / ID: 5sfz
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(ccnn1c2ccccc2)NC(=O)NCCc3c(oc(n3)c4ccccc4)C, micromolar IC50=0.843056
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-IV0 / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / Koerner, M. / 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)159,56116
Polymers157,6534
Non-polymers1,90912
Water9,080504
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8904
Polymers39,4131
Non-polymers4773
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)39,8904
Polymers39,4131
Non-polymers4773
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)39,8904
Polymers39,4131
Non-polymers4773
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)39,8904
Polymers39,4131
Non-polymers4773
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.195, 135.195, 234.845
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-IV0 / N-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethyl]-N'-(1-phenyl-1H-pyrazol-5-yl)urea


Mass: 387.434 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H21N5O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / 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: 53.05 %
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: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jun 4, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.16→43.49 Å / Num. obs: 85791 / % possible obs: 99.9 % / Redundancy: 4.416 % / Biso Wilson estimate: 43.297 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.104 / Rrim(I) all: 0.118 / Χ2: 0.865 / Net I/σ(I): 10.67 / Num. measured all: 378894 / Scaling rejects: 33
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
2.16-2.224.3311.0731.3727626637963780.4441.225100
2.22-2.284.3170.9981.5526608617161630.4971.14299.9
2.28-2.344.3890.712.0626327600059980.680.809100
2.34-2.414.410.5962.4625852586558620.7610.6899.9
2.41-2.494.4230.5042.9325073566956690.8110.574100
2.49-2.584.4260.3893.7924185546554640.8730.442100
2.58-2.684.4320.3044.8123521530953070.9120.346100
2.68-2.794.4390.2595.722534507850760.9340.295100
2.79-2.914.450.1997.1921880491849170.9670.227100
2.91-3.054.4610.168.9820673463546340.9760.182100
3.05-3.224.4660.12111.6819841444544430.9870.138100
3.22-3.424.4450.08915.3718535417141700.9930.101100
3.42-3.654.4240.06919.5317555397739680.9950.07999.8
3.65-3.944.3920.05722.9716129368136720.9960.06599.8
3.94-4.324.4270.04826.514781334133390.9970.05599.9
4.32-4.834.4440.04229.5313649307230710.9980.047100
4.83-5.584.4570.04129.1411980268926880.9980.046100
5.58-6.834.4860.0428.6310142226422610.9980.04699.9
6.83-9.664.4670.02936.017911177217710.9990.03399.9
9.66-43.494.3530.02540.1340929619400.9990.02997.8

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.16→43.49 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.932 / SU B: 6.948 / SU ML: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.236 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: ligand not fully occupied, use molecule A for modelling;
RfactorNum. reflection% reflectionSelection details
Rfree0.2349 4112 5 %RANDOM
Rwork0.1905 ---
obs0.1927 78338 96.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.75 Å2 / Biso mean: 39.198 Å2 / Biso min: 19.75 Å2
Baniso -1Baniso -2Baniso -3
1--0.47 Å2-0.24 Å20 Å2
2---0.47 Å20 Å2
3---1.54 Å2
Refinement stepCycle: final / Resolution: 2.16→43.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10148 0 124 504 10776
Biso mean--70.77 38.84 -
Num. residues----1250
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01310568
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179584
X-RAY DIFFRACTIONr_angle_refined_deg1.4171.65714307
X-RAY DIFFRACTIONr_angle_other_deg1.2971.56922285
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.73751256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.14322.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.518151857
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.951560
X-RAY DIFFRACTIONr_chiral_restr0.0710.21349
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211641
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022215
X-RAY DIFFRACTIONr_mcbond_it2.4074.0345006
X-RAY DIFFRACTIONr_mcbond_other2.4054.0335005
X-RAY DIFFRACTIONr_mcangle_it3.5246.0416253
LS refinement shellResolution: 2.16→2.216 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 313 -
Rwork0.339 5422 -
all-5735 -
obs--90.06 %

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