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- PDB-5sjg: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH C... -

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Basic information

Entry
Database: PDB / ID: 5sjg
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH C4CCN(c1cn(c(n1)CCc3nn2c(ncc(c2n3)C)C)C)C4=O, micromolar IC50=0.039238
Components(cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase ...) x 2
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 receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding ...3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of receptor guanylyl cyclase signaling pathway / cGMP catabolic process / cAMP catabolic process / regulation of cAMP/PKA signal transduction / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / : / cAMP binding / G alpha (s) signalling events / glutamatergic synapse / 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. / HD/PDEase domain / GAF-like domain superfamily
Similarity search - Domain/homology
Chem-K2L / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / 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)159,44516
Polymers157,7294
Non-polymers1,71612
Water10,178565
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,9184
Polymers39,4891
Non-polymers4293
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)39,8424
Polymers39,4131
Non-polymers4293
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)39,8424
Polymers39,4131
Non-polymers4293
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)39,8424
Polymers39,4131
Non-polymers4293
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.482, 135.482, 235.361
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number146
Space group name H-MH3

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Components

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CAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase ... , 2 types, 4 molecules ABCD

#1: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 39489.324 Da / Num. of mol.: 1
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: Protein cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A


Mass: 39413.203 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PDE10A / Plasmid: PET28a(+) / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q9Y233, 3',5'-cyclic-nucleotide phosphodiesterase

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Non-polymers , 4 types, 577 molecules

#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#5: Chemical
ChemComp-K2L / 1-(2-{2-[(4S)-5,8-dimethyl[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]ethyl}-1-methyl-1H-imidazol-4-yl)pyrrolidin-2-one


Mass: 339.395 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H21N7O / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 565 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 53.33 %
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: 0.99994 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 16, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99994 Å / Relative weight: 1
ReflectionResolution: 1.97→43.58 Å / Num. obs: 113690 / % possible obs: 99.8 % / Redundancy: 5.087 % / Biso Wilson estimate: 39.565 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07 / Rrim(I) all: 0.078 / Χ2: 0.89 / Net I/σ(I): 16.16 / Num. measured all: 578327 / Scaling rejects: 274
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
1.97-2.024.9491.0961.5141639842184140.5811.22899.9
2.02-2.084.670.8892.0737896819381140.6731.00699
2.08-2.145.2170.7222.5141807802480140.7810.80499.9
2.14-2.25.3150.433.8640896769576940.9040.477100
2.2-2.274.8840.4334.2536603755174940.9020.48799.2
2.27-2.355.1510.2775.9437744732873280.9530.309100
2.35-2.444.9540.2157.2434467695969580.9680.241100
2.44-2.544.9690.1828.6333827681168080.9770.204100
2.54-2.665.3730.14111.3934667645464520.9870.156100
2.66-2.795.2430.11613.7132302616261610.990.129100
2.79-2.945.3080.08916.9931297590158960.9950.09999.9
2.94-3.115.1250.07120.9528501556355610.9960.079100
3.11-3.334.940.05426.7225854523952340.9980.06199.9
3.33-3.65.2390.04334.7825323483748340.9980.04899.9
3.6-3.945.0380.03640.6922664450944990.9990.04199.8
3.94-4.415.0980.03146.1920560403640330.9990.03499.9
4.41-5.094.8280.02748.2117304358835840.9990.0399.9
5.09-6.235.4430.0284916384301130100.9990.031100
6.23-8.815.0440.0235211742233123280.9990.02699.9
8.81-43.585.3770.01863.146850128312740.9990.0299.3

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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: 1.97→43.58 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.936 / SU B: 4.72 / SU ML: 0.122 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.172 / ESU R Free: 0.161 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: carbonyl group of pyrrolidin-2-one anti to H-bond acceptor in triazole, as expected;
RfactorNum. reflection% reflectionSelection details
Rfree0.2242 4940 5 %RANDOM
Rwork0.1761 ---
obs0.1784 93802 86.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 112.56 Å2 / Biso mean: 35.422 Å2 / Biso min: 18.83 Å2
Baniso -1Baniso -2Baniso -3
1--0.17 Å2-0.08 Å20 Å2
2---0.17 Å20 Å2
3---0.54 Å2
Refinement stepCycle: final / Resolution: 1.97→43.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10165 0 108 565 10838
Biso mean--31.18 36.38 -
Num. residues----1252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.01310588
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179914
X-RAY DIFFRACTIONr_angle_refined_deg1.7451.65714359
X-RAY DIFFRACTIONr_angle_other_deg1.4371.58522869
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.05651268
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.49322.563554
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.028151858
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.7681558
X-RAY DIFFRACTIONr_chiral_restr0.0890.21355
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212232
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022452
X-RAY DIFFRACTIONr_mcbond_it3.2023.5185024
X-RAY DIFFRACTIONr_mcbond_other3.2033.5165022
X-RAY DIFFRACTIONr_mcangle_it4.2115.2596278
LS refinement shellResolution: 1.97→2.021 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 372 -
Rwork0.312 7238 -
all-7610 -
obs--90.6 %

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