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- PDB-5sfd: CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH n... -

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Basic information

Entry
Database: PDB / ID: 5sfd
TitleCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 10 IN COMPLEX WITH n1(nc(nc1CCc2nn3c(n2)c(ncc3C)C)N4CCCCC4)C, micromolar IC50=0.03165
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


extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cAMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding ...extrinsic component of postsynaptic density membrane / 3',5'-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cGMP-inhibited cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / cAMP catabolic process / cGMP effects / 3',5'-cyclic-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP-mediated signaling / cAMP binding / G alpha (s) signalling events / perikaryon / 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-IKB / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.05 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
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)159,37316
Polymers157,6534
Non-polymers1,72112
Water7,638424
1
A: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
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)39,8434
Polymers39,4131
Non-polymers4303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)135.026, 135.026, 235.566
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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-IKB / (4S)-5,8-dimethyl-2-{2-[1-methyl-3-(piperidin-1-yl)-1H-1,2,4-triazol-5-yl]ethyl}[1,2,4]triazolo[1,5-a]pyrazine


Mass: 340.426 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H24N8
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 424 / 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: 2.62 Å3/Da / Density % sol: 53.08 %
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: 1.00004 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 2.05→43.7 Å / Num. obs: 100361 / % possible obs: 99.9 % / Redundancy: 5.169 % / Biso Wilson estimate: 43.74 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 15.25
Reflection shellResolution: 2.05→2.1 Å / Redundancy: 5.15 % / Rmerge(I) obs: 1.374 / Mean I/σ(I) obs: 1.3 / % possible all: 99.6

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0258refinement
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INHOUSE MODEL

Resolution: 2.05→43.7 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.907 / SU B: 4.968 / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.184 / ESU R Free: 0.169 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: ORIENTATION OF PSEUDO-SYMMETRIC PIPERIDYLPYRAZOLE DICTATED BY WATER MOLECULE THAT HYDROGEN BONDS TO PYRIDINE N-ATOM
RfactorNum. reflection% reflectionSelection details
Rfree0.231 4722 5 %RANDOM
Rwork0.182 ---
obs0.184 90254 94.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.44 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å2-0.17 Å20 Å2
2---0.34 Å20 Å2
3---1.11 Å2
Refinement stepCycle: LAST / Resolution: 2.05→43.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10148 0 108 424 10680
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01310533
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179644
X-RAY DIFFRACTIONr_angle_refined_deg1.8811.65614270
X-RAY DIFFRACTIONr_angle_other_deg1.4661.58222427
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.38151251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.10822.614547
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.707151848
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6581556
X-RAY DIFFRACTIONr_chiral_restr0.0930.21347
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211579
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022197
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.8593.8715004
X-RAY DIFFRACTIONr_mcbond_other3.8563.875002
X-RAY DIFFRACTIONr_mcangle_it4.8315.7916249
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.1 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.526 273 -
Rwork0.442 5501 -
obs--77.88 %

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