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

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Basic information

Entry
Database: PDB / ID: 5sif
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH C1=CN(N=C(C1=O)c2ccnn2c3cc(ccc3F)F)c4cc(ccc4)[S](=O)(=O)C, micromolar IC50=0.049318
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-JOO / PRASEODYMIUM ION / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsJoseph, C. / Benz, J. / Flohr, A. / Rogers-Evans, M. / 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 1.2Aug 21, 2024Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.pdbx_collection_date
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification
Revision 1.4Oct 16, 2024Group: Structure summary / Category: struct / Item: _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)160,98026
Polymers157,6534
Non-polymers3,32722
Water9,890549
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,0596
Polymers39,4131
Non-polymers6465
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)40,6369
Polymers39,4131
Non-polymers1,2238
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)40,3547
Polymers39,4131
Non-polymers9416
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)39,9314
Polymers39,4131
Non-polymers5183
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.135, 135.135, 235.085
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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Protein , 1 types, 4 molecules ABCD

#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

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Non-polymers , 7 types, 571 molecules

#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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-JOO / 3-[1-(2,5-difluorophenyl)-1H-pyrazol-5-yl]-1-[3-(methanesulfonyl)phenyl]pyridazin-4(1H)-one


Mass: 428.412 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H14F2N4O3S / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-PR / PRASEODYMIUM ION


Mass: 140.908 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Pr
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 549 / 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: 2.62 Å3/Da / Density % sol: 53.06 %
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 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 2, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0 Å / Relative weight: 1
ReflectionResolution: 2.2→41.47 Å / Num. obs: 76856 / % possible obs: 94.5 % / Redundancy: 0.95 % / Rmerge(I) obs: 0.096 / Rsym value: 0.096 / Net I/σ(I): 7.97
Reflection shellResolution: 2.2→2.3 Å / Redundancy: 1.26 % / Rmerge(I) obs: 0.372 / Mean I/σ(I) obs: 1.39 / Rsym value: 0.372 / % possible all: 87.7

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
DENZOdata reduction
SADABSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: inhouse model

Resolution: 2.2→41.45 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.934 / SU B: 7.203 / SU ML: 0.168 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.282 / ESU R Free: 0.215 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: a minor fraction of the difluorophenyl group may be rotated by 180 degrees;
RfactorNum. reflection% reflectionSelection details
Rfree0.2309 3575 5 %RANDOM
Rwork0.1817 ---
obs0.1841 68250 88.33 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 164.12 Å2 / Biso mean: 37.861 Å2 / Biso min: 13.75 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0.02 Å20 Å2
2---0.03 Å20 Å2
3---0.11 Å2
Refinement stepCycle: final / Resolution: 2.2→41.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10156 0 143 549 10848
Biso mean--49.84 39.36 -
Num. residues----1252
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.01310552
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179557
X-RAY DIFFRACTIONr_angle_refined_deg1.4121.65914296
X-RAY DIFFRACTIONr_angle_other_deg1.2851.56922223
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.91951250
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.30922.555548
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.835151847
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3341557
X-RAY DIFFRACTIONr_chiral_restr0.0680.21349
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211601
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022198
X-RAY DIFFRACTIONr_mcbond_it2.33.8945006
X-RAY DIFFRACTIONr_mcbond_other2.2973.8935004
X-RAY DIFFRACTIONr_mcangle_it3.3715.8346251
LS refinement shellResolution: 2.2→2.257 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 224 -
Rwork0.301 3993 -
all-4217 -
obs--69.45 %

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