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

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Basic information

Entry
Database: PDB / ID: 5seq
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(nn(c(n1)CCc2nn3c(n2)c(nc(c3C)C)C)C)N4CCCC4, micromolar IC50=0.037262
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE inhibitor / PHOSPHODIESTERASE / PDE10 / HYDROLASE / 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-IGO / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsJoseph, C. / Lerner, C. / 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)159,37316
Polymers157,6534
Non-polymers1,72112
Water7,098394
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.275, 135.275, 235.377
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-IGO / (4S)-5,6,8-trimethyl-2-{2-[1-methyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl]ethyl}[1,2,4]triazolo[1,5-a]pyrazine


Mass: 340.426 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H24N8 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 394 / 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: 2.63 Å3/Da / Density % sol: 53.21 %
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: 0.99979 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 10, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99979 Å / Relative weight: 1
ReflectionResolution: 2.18→43.68 Å / Num. obs: 83714 / % possible obs: 99.9 % / Redundancy: 4.261 % / Biso Wilson estimate: 52.683 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Rrim(I) all: 0.066 / Χ2: 0.867 / Net I/σ(I): 16.86 / Num. measured all: 356676 / Scaling rejects: 24
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
2.18-2.244.3281.0621.4126780619061870.5251.21100
2.24-2.34.30.8471.7826112608460730.6280.96799.8
2.3-2.364.240.6452.3124804585658500.7450.73899.9
2.36-2.444.0270.5072.8222912569556900.820.58599.9
2.44-2.524.1740.423.4823179555755530.8710.48299.9
2.52-2.614.3990.3034.8623458533553320.9270.34599.9
2.61-2.74.3860.2396.0922717518151790.9510.272100
2.7-2.814.2850.1927.3421243496349570.9690.21999.9
2.81-2.944.0860.1479.319361474547380.9790.16999.9
2.94-3.084.1470.11411.9418988458545790.9870.13199.9
3.08-3.254.4210.08316.6319155433443330.9940.095100
3.25-3.454.3960.05823.0517965409240870.9970.06699.9
3.45-3.684.3060.04230.5516496383938310.9980.04799.8
3.68-3.984.0820.03237.8814655359235900.9990.03799.9
3.98-4.364.3560.02745.8314282328032790.9990.03100
4.36-4.874.3940.02352.313098298629810.9990.02699.8
4.87-5.634.1210.02450.4810846263426320.9990.02799.9
5.63-6.894.2760.02351.479454221222110.9990.027100
6.89-9.754.2930.01765.1773321715170810.01999.6
9.75-43.684.1550.01672.31383993792410.01898.6

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Processing

Software
NameVersionClassificationNB
XSCALEdata scaling
REFMAC5.8.0267refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.18→43.68 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.948 / SU B: 6.491 / SU ML: 0.154 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.216 / ESU R Free: 0.191 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2291 4085 5 %RANDOM
Rwork0.1723 ---
obs0.1751 76880 96.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 136.84 Å2 / Biso mean: 50.454 Å2 / Biso min: 28.5 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å2-0.17 Å20 Å2
2---0.34 Å20 Å2
3---1.12 Å2
Refinement stepCycle: final / Resolution: 2.18→43.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10167 0 108 394 10669
Biso mean--45.12 47.86 -
Num. residues----1253
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.01310531
X-RAY DIFFRACTIONr_bond_other_d0.0020.0179879
X-RAY DIFFRACTIONr_angle_refined_deg1.6861.64514265
X-RAY DIFFRACTIONr_angle_other_deg1.3671.58722773
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.23451249
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.61222.614547
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.487151847
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.9291556
X-RAY DIFFRACTIONr_chiral_restr0.0830.21346
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211745
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022427
X-RAY DIFFRACTIONr_mcbond_it4.3785.1085008
X-RAY DIFFRACTIONr_mcbond_other4.3755.1075006
X-RAY DIFFRACTIONr_mcangle_it5.757.6466253
LS refinement shellResolution: 2.18→2.237 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 304 -
Rwork0.336 5280 -
all-5584 -
obs--90.47 %

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