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

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Basic information

Entry
Database: PDB / ID: 5sgl
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(ccc(cc1)[C@H](OCC)C(=O)N\\N=C\\c2cc(c(Br)c(c2)OC)OC)n3nccc3, micromolar IC50=0.001626
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'-cGMP-inhibited 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'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited 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 / Metal dependent phosphohydrolases with conserved 'HD' motif. / GAF-like domain superfamily / HD/PDEase domain
Similarity search - Domain/homology
Chem-IXT / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.28 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / Groebke-Zbinden, K. / 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

Downloads & links

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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)159,96116
Polymers157,6534
Non-polymers2,30812
Water6,810378
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9904
Polymers39,4131
Non-polymers5773
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)39,9904
Polymers39,4131
Non-polymers5773
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)39,9904
Polymers39,4131
Non-polymers5773
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)39,9904
Polymers39,4131
Non-polymers5773
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.574, 135.574, 235.517
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-IXT / (2S)-N'-[(E)-(4-bromo-3,5-dimethoxyphenyl)methylidene]-2-ethoxy-2-[4-(1H-pyrazol-1-yl)phenyl]acetohydrazide


Mass: 487.346 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H23BrN4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 378 / 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: 53.45 %
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: Jun 24, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.28→43.72 Å / Num. obs: 73542 / % possible obs: 99.9 % / Redundancy: 5.212 % / Biso Wilson estimate: 52.581 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.118 / Rrim(I) all: 0.132 / Χ2: 0.835 / Net I/σ(I): 10.1 / Num. measured all: 383278 / Scaling rejects: 49
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
2.28-2.344.8941.4221.2326761548154680.4311.59599.8
2.34-2.45.0061.1971.4726429528752790.5331.33999.8
2.4-2.475.3390.981.8527407513751330.6311.08899.9
2.47-2.555.3530.8272.2226855502050170.7150.91799.9
2.55-2.635.3410.6432.8825941485948570.8020.713100
2.63-2.735.2430.523.4724571468646860.8550.579100
2.73-2.835.0460.4354.0723152459145880.8860.48699.9
2.83-2.945.0760.3445.0621849431043040.9290.38499.9
2.94-3.075.4060.2716.5322898424242360.9550.399.9
3.07-3.225.4120.1978.5421441396439620.9770.21999.9
3.22-3.45.3760.14311.5320456380838050.9870.15899.9
3.4-3.615.210.10315.2718768360436020.9920.11599.9
3.61-3.854.9410.08318.0416712338433820.9930.09399.9
3.85-4.165.3830.06622.6916887314131370.9960.07399.9
4.16-4.565.3770.05625.5315534289128890.9970.06299.9
4.56-5.15.2480.0527.3913728261726160.9980.055100
5.1-5.894.8690.05225.311321232723250.9970.05999.9
5.89-7.215.490.04828.1910601193119310.9980.054100
7.21-10.25.0770.03535.217686152215140.9990.03999.5
10.2-43.725.2790.03339.8542818228110.9990.03698.7

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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: 2.28→43.72 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.941 / SU B: 8.462 / SU ML: 0.186 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.282 / ESU R Free: 0.216 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: Pr3+ not modeled; Electon density requires S-enantiomer and cis-amide; R-enantiomer with trans-amide possible but worse fit to electron density;
RfactorNum. reflection% reflectionSelection details
Rfree0.2301 3516 5 %RANDOM
Rwork0.1808 ---
obs0.1832 67206 96.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 119.55 Å2 / Biso mean: 45.308 Å2 / Biso min: 20.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å2-0.09 Å20 Å2
2---0.17 Å20 Å2
3---0.56 Å2
Refinement stepCycle: final / Resolution: 2.28→43.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10176 0 132 378 10686
Biso mean--46.78 41.73 -
Num. residues----1255
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01310587
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179592
X-RAY DIFFRACTIONr_angle_refined_deg1.4831.65814330
X-RAY DIFFRACTIONr_angle_other_deg1.311.56922301
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.91851257
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.9222.464552
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.493151855
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8141559
X-RAY DIFFRACTIONr_chiral_restr0.0720.21357
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211656
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022213
X-RAY DIFFRACTIONr_mcbond_it3.2664.6665022
X-RAY DIFFRACTIONr_mcbond_other3.2584.6655020
X-RAY DIFFRACTIONr_mcangle_it4.7056.996272
LS refinement shellResolution: 2.28→2.339 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.422 252 -
Rwork0.349 4612 -
all-4864 -
obs--89.07 %

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