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- PDB-5sfh: Crystal Structure of human phosphodiesterase 10 in complex with N... -

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Basic information

Entry
Database: PDB / ID: 5sfh
TitleCrystal Structure of human phosphodiesterase 10 in complex with N-cyclopropyl-5-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl]-N,1-dimethyl-1,2,4-triazol-3-amine
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


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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity ...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-GMP phosphodiesterase activity / cGMP binding / 3',5'-cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / G alpha (s) signalling events / signal transduction / metal ion binding / cytosol
Similarity search - Function
3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / Domain present in phytochromes and cGMP-specific phosphodiesterases. / GAF domain ...3'5'-cyclic nucleotide phosphodiesterase / GAF domain / 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. / 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-IKO / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsJoseph, C. / Flohr, A. / 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

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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)159,31716
Polymers157,6534
Non-polymers1,66412
Water6,161342
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A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8294
Polymers39,4131
Non-polymers4163
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)39,8294
Polymers39,4131
Non-polymers4163
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)39,8294
Polymers39,4131
Non-polymers4163
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)39,8294
Polymers39,4131
Non-polymers4163
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.463, 135.463, 235.776
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-IKO / N-cyclopropyl-5-{2-[(4S)-5,8-dimethyl[1,2,4]triazolo[1,5-a]pyrazin-2-yl]ethyl}-N,1-dimethyl-1H-1,2,4-triazol-3-amine


Mass: 326.399 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H22N8 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 342 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 53.42 %
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: 0.99999 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Feb 5, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 2.29→43.75 Å / Num. obs: 72627 / % possible obs: 99.9 % / Redundancy: 5.217 % / Biso Wilson estimate: 55.367 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.085 / Rrim(I) all: 0.095 / Χ2: 0.847 / Net I/σ(I): 13.75 / Num. measured all: 378895 / Scaling rejects: 23
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
2.29-2.355.2891.3181.328476538653840.4941.465100
2.35-2.415.3311.0461.6328103527452720.5991.161100
2.41-2.485.3040.8661.9626892507450700.6990.96299.9
2.48-2.565.2130.6952.4425744494049380.7750.774100
2.56-2.645.1040.5333.1224608482448210.8350.59499.9
2.64-2.744.8950.4413.7422760465246500.8780.494100
2.74-2.845.0680.3524.7322613446644620.9250.39399.9
2.84-2.965.4020.2646.3623190429442930.9620.292100
2.96-3.095.3680.2038.1522254414841460.9750.225100
3.09-3.245.3230.14710.8820935393339330.9870.163100
3.24-3.415.2170.10414.9519502373837380.9930.116100
3.41-3.624.9670.07319.7717592354435420.9960.08299.9
3.62-3.875.2550.0572617577334533450.9970.063100
3.87-4.185.4220.04532.5916880311531130.9980.0599.9
4.18-4.585.320.03936.4415061283128310.9990.044100
4.58-5.124.9110.03638.2112725259225910.9990.04100
5.12-5.915.1240.03737.1611709228622850.9990.041100
5.91-7.245.4530.03440.7610459191819180.9990.037100
7.24-10.245.010.02351.487450149014870.9990.02699.8
10.24-43.755.4020.0258.91436581780810.02298.9

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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: 2.29→43.75 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.947 / SU B: 7.85 / SU ML: 0.176 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.274 / ESU R Free: 0.209 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: check all ligand conformations in the four protomers rotation of 5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin dictated by hydrogen bond to water molecule
RfactorNum. reflection% reflectionSelection details
Rfree0.2213 3484 5 %RANDOM
Rwork0.1738 ---
obs0.1762 66519 96.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 119.56 Å2 / Biso mean: 49.806 Å2 / Biso min: 25.39 Å2
Baniso -1Baniso -2Baniso -3
1--0.5 Å2-0.25 Å2-0 Å2
2---0.5 Å20 Å2
3---1.64 Å2
Refinement stepCycle: final / Resolution: 2.29→43.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10159 0 104 342 10605
Biso mean--53.46 46.65 -
Num. residues----1252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01310544
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179662
X-RAY DIFFRACTIONr_angle_refined_deg1.4511.65614288
X-RAY DIFFRACTIONr_angle_other_deg1.2831.58122459
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.89551254
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16122.523551
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.019151853
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.031558
X-RAY DIFFRACTIONr_chiral_restr0.0710.21353
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211589
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022209
X-RAY DIFFRACTIONr_mcbond_it3.4085.1315010
X-RAY DIFFRACTIONr_mcbond_other3.3965.135008
X-RAY DIFFRACTIONr_mcangle_it4.7847.6846257
LS refinement shellResolution: 2.29→2.349 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.358 268 -
Rwork0.329 4554 -
all-4822 -
obs--89.8 %

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