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- PDB-3qpp: Structure of PDE10-inhibitor complex -

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Basic information

Entry
Database: PDB / ID: 3qpp
TitleStructure of PDE10-inhibitor complex
ComponentscAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Phosphodiesterase Inhibitors / Structure-based drug design / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process ...regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / negative regulation of cAMP-mediated signaling / cGMP-stimulated cyclic-nucleotide phosphodiesterase activity / 3',5'-cyclic-nucleotide phosphodiesterase / negative regulation of cGMP-mediated signaling / cGMP catabolic process / 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 / perikaryon / neuronal cell body / signal transduction / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain / GAF domain / 3'5'-cyclic nucleotide phosphodiesterase / Domain present in phytochromes and cGMP-specific phosphodiesterases. / 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 / GAF-like domain superfamily / Metal dependent phosphohydrolases with conserved 'HD' motif. / HD/PDEase domain / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-PFW / cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.8 Å
AuthorsPandit, J. / Marr, E.S.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Use of Structure-Based Design to Discover a Potent, Selective, In Vivo Active Phosphodiesterase 10A Inhibitor Lead Series for the Treatment of Schizophrenia.
Authors: Helal, C.J. / Kang, Z. / Hou, X. / Pandit, J. / Chappie, T.A. / Humphrey, J.M. / Marr, E.S. / Fennell, K.F. / Chenard, L.K. / Fox, C. / Schmidt, C.J. / Williams, R.D. / Chapin, D.S. / ...Authors: Helal, C.J. / Kang, Z. / Hou, X. / Pandit, J. / Chappie, T.A. / Humphrey, J.M. / Marr, E.S. / Fennell, K.F. / Chenard, L.K. / Fox, C. / Schmidt, C.J. / Williams, R.D. / Chapin, D.S. / Siuciak, J. / Lebel, L. / Menniti, F. / Cianfrogna, J. / Fonseca, K.R. / Nelson, F.R. / O'Connor, R. / Macdougall, M. / McDowell, L. / Liras, S.
History
DepositionFeb 14, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 15, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 20, 2011Group: Database references
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,4947
Polymers41,6621
Non-polymers8336
Water5,188288
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.616, 120.616, 84.008
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, 1 molecules A

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


Mass: 41661.715 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Pde10a / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9QYJ6, 3',5'-cyclic-nucleotide phosphodiesterase, 3',5'-cyclic-GMP phosphodiesterase

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Non-polymers , 6 types, 294 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical ChemComp-PFW / 7-methoxy-4-[(3S)-3-phenylpiperidin-1-yl]-6-[2-(quinolin-2-yl)ethoxy]quinazoline


Mass: 490.596 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30N4O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 288 / Source method: isolated from a natural source / Formula: H2O

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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: 2.82 Å3/Da / Density % sol: 56.43 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Details: VariMax Optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionRedundancy: 5.35 % / Number: 265639 / Rmerge(I) obs: 0.102 / Χ2: 0.98 / D res high: 1.71 Å / D res low: 60.31 Å / Num. obs: 49243 / % possible obs: 100
Diffraction reflection shell

ID: 1

Highest resolution (Å)Lowest resolution (Å)% possible obs (%)Rmerge(I) obsChi squaredRedundancyRejects
3.6860.311000.0851.465.461035
2.923.681000.0951.195.49408
2.552.921000.1031.095.47267
2.322.551000.1191.055.44147
2.152.321000.1451.035.4193
2.032.151000.1890.935.3829
1.932.031000.2470.795.334
1.841.931000.3070.755.287
1.771.841000.3470.715.24
1.711.7799.80.3740.715.053
ReflectionResolution: 1.71→65.94 Å / Num. obs: 49243 / % possible obs: 100 % / Redundancy: 5.35 % / Rmerge(I) obs: 0.102 / Χ2: 0.98 / Net I/σ(I): 8.6 / Scaling rejects: 1993
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
1.71-1.775.050.3743.12467148830.7199.8
1.77-1.845.240.3473.42581149300.71100
1.84-1.935.280.3073.92614149500.75100
1.93-2.035.330.2474.82648049690.79100
2.03-2.155.380.1896.52628848810.93100
2.15-2.325.410.1458.62668549181.03100
2.32-2.555.440.11910.52696949341.05100
2.55-2.925.470.10312.62714049141.09100
2.92-3.685.490.09513.72745649241.19100
3.68-60.315.460.08517.42799849401.46100

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Processing

Software
NameVersionClassificationNB
d*TREK8.0SSIdata scaling
REFMACrefinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.8→60.31 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.951 / WRfactor Rfree: 0.216 / WRfactor Rwork: 0.1853 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.8526 / SU B: 2.945 / SU ML: 0.086 / SU R Cruickshank DPI: 0.1082 / SU Rfree: 0.1046 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.105 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2105 3241 7.7 %RANDOM
Rwork0.1836 ---
obs0.1857 42245 99.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 73.71 Å2 / Biso mean: 31.9469 Å2 / Biso min: 18.75 Å2
Baniso -1Baniso -2Baniso -3
1--1.41 Å2-0.71 Å20 Å2
2---1.41 Å20 Å2
3---2.12 Å2
Refinement stepCycle: LAST / Resolution: 1.8→60.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2477 0 52 288 2817
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0212590
X-RAY DIFFRACTIONr_angle_refined_deg1.2591.9613507
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9065304
X-RAY DIFFRACTIONr_chiral_restr0.0880.2377
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021953
X-RAY DIFFRACTIONr_nbd_refined0.2160.21307
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2244
X-RAY DIFFRACTIONr_metal_ion_refined0.1610.23
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1490.236
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1240.219
X-RAY DIFFRACTIONr_mcbond_it0.7541.51525
X-RAY DIFFRACTIONr_mcangle_it1.4222472
X-RAY DIFFRACTIONr_scbond_it2.29431065
X-RAY DIFFRACTIONr_scangle_it3.7044.51035
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.367 244
Rwork0.331 2870
all-3114

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