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- PDB-5sgx: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH N... -

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Basic information

Entry
Database: PDB / ID: 5sgx
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH N4(c1nn(c(n1)CCc3nn2c(ncc(C)c2n3)C)C)CCC[C@@H]4C(F)(F)F, micromolar IC50=0.027384
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 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-IZH / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 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)159,74116
Polymers157,8054
Non-polymers1,93612
Water14,196788
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8974
Polymers39,4131
Non-polymers4843
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)39,9734
Polymers39,4891
Non-polymers4843
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)39,8974
Polymers39,4131
Non-polymers4843
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)39,9734
Polymers39,4891
Non-polymers4843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.599, 135.599, 235.562
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 ACBD

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


Mass: 39413.203 Da / Num. of mol.: 2
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) / 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: 39489.324 Da / Num. of mol.: 2
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, 800 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-IZH / (4S)-5,8-dimethyl-2-(2-{1-methyl-3-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-1,2,4-triazol-5-yl}ethyl)[1,2,4]triazolo[1,5-c]pyrimidine


Mass: 394.397 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H21F3N8 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 788 / 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: 53.43 %
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: 0.99997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 1.93→43.72 Å / Num. obs: 121432 / % possible obs: 100 % / Redundancy: 5.202 % / Biso Wilson estimate: 41.17 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06 / Rrim(I) all: 0.067 / Χ2: 0.872 / Net I/σ(I): 18 / Num. measured all: 631711 / Scaling rejects: 25
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
1.93-1.985.2351.2591.3447418906590580.481.40199.9
1.98-2.035.160.911.8444884870186990.6411.014100
2.03-2.094.910.6762.4641948854985430.7580.75899.9
2.09-2.165.0840.5283.241985826082590.8460.589100
2.16-2.235.3720.3674.6343105802880240.9180.407100
2.23-2.315.3260.3025.641579780778070.9440.335100
2.31-2.395.2430.2297.1538709738673830.9650.255100
2.39-2.495.0570.1838.636426720572030.9760.204100
2.49-2.64.9880.14110.9434598693769360.9860.158100
2.6-2.735.3660.11413.8835299657965780.9910.127100
2.73-2.885.3870.09116.9633946630163010.9950.101100
2.88-3.055.3280.0721.7931528592059170.9960.07799.9
3.05-3.265.0390.05127.9228276561256110.9980.058100
3.26-3.525.2040.03837.9526777514651450.9990.042100
3.52-3.865.4660.0348.2626156478647850.9990.033100
3.86-4.325.3130.02555.9922917431543130.9990.027100
4.32-4.984.9460.02259.218918382638250.9990.025100
4.98-6.15.370.02358.9817276321732170.9990.025100
6.1-8.635.2130.0264.49128612468246710.022100
8.63-43.725.220.01581.8871051371136110.01699.3

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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: 1.93→43.72 Å / Cor.coef. Fo:Fc: 0.971 / Cor.coef. Fo:Fc free: 0.952 / SU B: 4.115 / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.137 / ESU R Free: 0.136 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2159 5912 5 %RANDOM
Rwork0.1683 ---
obs0.1707 111863 96.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 126 Å2 / Biso mean: 36.606 Å2 / Biso min: 19.62 Å2
Baniso -1Baniso -2Baniso -3
1--0.36 Å2-0.18 Å20 Å2
2---0.36 Å20 Å2
3---1.17 Å2
Refinement stepCycle: final / Resolution: 1.93→43.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10197 0 120 788 11105
Biso mean--34.08 41.87 -
Num. residues----1258
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.01310712
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179780
X-RAY DIFFRACTIONr_angle_refined_deg1.761.6614542
X-RAY DIFFRACTIONr_angle_other_deg1.4721.5822771
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.83751294
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.96422.598562
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.07151877
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4121559
X-RAY DIFFRACTIONr_chiral_restr0.0940.21378
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212116
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022237
X-RAY DIFFRACTIONr_mcbond_it3.5453.6635068
X-RAY DIFFRACTIONr_mcbond_other3.5423.6635067
X-RAY DIFFRACTIONr_mcangle_it4.5255.4746338
LS refinement shellResolution: 1.93→1.98 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.389 447 -
Rwork0.347 7737 -
all-8184 -
obs--90.48 %

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