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

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Basic information

Entry
Database: PDB / ID: 5sfr
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH c1(c(C(=O)N(C)CC)cnn1C)C(Nc3nc2nc(cn2cc3)c4cc(ccc4)OCCF)=O, micromolar IC50=0.006128
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-IOI / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsJoseph, C. / Gobbi, L. / 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)159,87416
Polymers157,6534
Non-polymers2,22112
Water10,899605
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9684
Polymers39,4131
Non-polymers5553
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)39,9684
Polymers39,4131
Non-polymers5553
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)39,9684
Polymers39,4131
Non-polymers5553
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)39,9684
Polymers39,4131
Non-polymers5553
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.625, 135.625, 235.847
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-IOI / N~4~-ethyl-N~5~-{(4S)-2-[3-(2-fluoroethoxy)phenyl]imidazo[1,2-a]pyrimidin-7-yl}-N~4~,1-dimethyl-1H-pyrazole-4,5-dicarboxamide


Mass: 465.480 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H24FN7O3 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 605 / 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: 2.65 Å3/Da / Density % sol: 53.55 %
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: Jul 17, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.748
11K, H, -L20.252
ReflectionResolution: 2.04→43.77 Å / Num. obs: 103018 / % possible obs: 100 % / Redundancy: 5.166 % / Biso Wilson estimate: 45.248 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.119 / Rrim(I) all: 0.133 / Χ2: 0.857 / Net I/σ(I): 8.16 / Num. measured all: 532187 / Scaling rejects: 15
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
2.04-2.094.9551.4821.0938137769576960.3211.659100
2.09-2.155.0871.1411.4437700741174110.4461.273100
2.15-2.215.410.782.1739046721972180.6350.864100
2.21-2.285.3810.652.637854703570350.7030.721100
2.28-2.365.3240.493.3636114678567830.8050.544100
2.36-2.445.2510.44.0734555658165810.8640.445100
2.44-2.535.0050.3444.5631596631363130.8830.385100
2.53-2.635.1360.266.0931497613361330.9270.29100
2.63-2.755.4240.2127.5431482580458040.9490.235100
2.75-2.885.3480.1748.7730196564656460.9670.193100
2.88-3.045.2680.14310.5327907529952970.9760.159100
3.04-3.235.050.11712.3825479504850450.9810.13199.9
3.23-3.454.8670.09714.5123060473847380.9850.109100
3.45-3.725.2610.08617.0523264442244220.9870.096100
3.72-4.085.1340.08118.0420753404340420.9880.09100
4.08-4.564.9350.07818.5617998365636470.9890.08799.8
4.56-5.274.6910.07518.4615141323332280.9880.08499.8
5.27-6.455.2110.07719.0914206272627260.9890.086100
6.45-9.124.8710.0719.1810273211121090.9920.07999.9
9.12-43.775.1830.06520.525929115511440.9920.07299

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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: 2.04→43.77 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.949 / SU B: 3.415 / SU ML: 0.096 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.036 / ESU R Free: 0.031 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: terminal fluorine mobile some close contacts with nearby (disordered) glutamate inhibitor well defined by electron density
RfactorNum. reflection% reflectionSelection details
Rfree0.2127 5173 5 %RANDOM
Rwork0.1814 ---
obs0.1829 97575 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 114.49 Å2 / Biso mean: 37.803 Å2 / Biso min: 19.7 Å2
Baniso -1Baniso -2Baniso -3
1--0.41 Å2-0 Å2-0 Å2
2---0.41 Å2-0 Å2
3---0.83 Å2
Refinement stepCycle: final / Resolution: 2.04→43.77 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10152 0 144 605 10901
Biso mean--35.81 40.29 -
Num. residues----1251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01310588
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179584
X-RAY DIFFRACTIONr_angle_refined_deg1.7671.66114341
X-RAY DIFFRACTIONr_angle_other_deg1.4211.56922283
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.06551255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.49622.419554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.754151856
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7291560
X-RAY DIFFRACTIONr_chiral_restr0.0930.21348
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0211729
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022215
X-RAY DIFFRACTIONr_mcbond_it4.023.8375008
X-RAY DIFFRACTIONr_mcbond_other4.0183.8355006
X-RAY DIFFRACTIONr_mcangle_it4.7925.7386255
LS refinement shellResolution: 2.04→2.093 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.726 349 -
Rwork0.694 7336 -
all-7685 -
obs--99.87 %

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