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

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Basic information

Entry
Database: PDB / ID: 3qpo
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


cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 ...cyclic-nucleotide phosphodiesterase activity / cGMP effects / G alpha (s) signalling events / regulation of protein kinase A signaling / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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-nucleotide phosphodiesterase activity / cGMP binding / 3',5'-cyclic-GMP phosphodiesterase activity / 3',5'-cyclic-AMP phosphodiesterase activity / cAMP binding / cAMP-mediated signaling / perikaryon / neuronal cell body / metal ion binding / cytosol
Similarity search - Function
Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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. ...Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b / 3'5'-cyclic nucleotide phosphodiesterase, catalytic 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-PFR / 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.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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)42,3846
Polymers41,6621
Non-polymers7225
Water3,171176
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)120.451, 120.451, 82.061
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
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 , 5 types, 181 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-PFR / 7-methoxy-4-[(3S)-3-phenylpiperidin-1-yl]-6-[2-(pyridin-2-yl)ethoxy]quinazoline


Mass: 440.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28N4O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / 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: 2.75 Å3/Da / Density % sol: 55.27 %

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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: 5.34 % / Number: 228533 / Rmerge(I) obs: 0.09 / Χ2: 0.98 / D res high: 1.78 Å / D res low: 38.18 Å / Num. obs: 42514 / % possible obs: 100
Diffraction reflection shell

ID: 1 / % possible obs: 100 %

Highest resolution (Å)Lowest resolution (Å)Rmerge(I) obsChi squaredRedundancyRejects
3.8338.180.0470.945.6853
3.043.830.0610.935.63484
2.663.040.10.975.66164
2.422.660.14115.63106
2.242.420.1861.015.5835
2.112.240.2341.015.5422
22.110.2981.055.4927
1.9220.3691.035.3717
1.841.920.390.944.823
1.781.840.3890.874.033
ReflectionResolution: 1.78→64.55 Å / Num. obs: 42514 / % possible obs: 100 % / Redundancy: 5.34 % / Rmerge(I) obs: 0.09 / Χ2: 0.98 / Net I/σ(I): 9.7 / Scaling rejects: 1714
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2
1.78-1.844.030.3893.21702842280.87
1.84-1.924.820.393.52070142910.94
1.92-25.370.36942265842151.03
2-2.115.490.2984.72342842661.05
2.11-2.245.540.2345.62345642301.01
2.24-2.425.580.1866.92386542681.01
2.42-2.665.630.1418.92397042421
2.66-3.045.660.111.92432142660.97
3.04-3.835.630.06119.22445642600.93
3.83-38.185.60.047262465042480.94

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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→38.18 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.942 / WRfactor Rfree: 0.228 / WRfactor Rwork: 0.1956 / Occupancy max: 1 / Occupancy min: 0.5 / FOM work R set: 0.7602 / SU B: 3.996 / SU ML: 0.108 / SU R Cruickshank DPI: 0.1198 / SU Rfree: 0.117 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.117 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2364 3160 7.7 %RANDOM
Rwork0.2043 ---
obs0.2069 41136 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: 73.55 Å2 / Biso mean: 30.9401 Å2 / Biso min: 14.79 Å2
Baniso -1Baniso -2Baniso -3
1--1.42 Å2-0.71 Å20 Å2
2---1.42 Å20 Å2
3---2.13 Å2
Refinement stepCycle: LAST / Resolution: 1.8→38.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2477 0 45 176 2698
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0212610
X-RAY DIFFRACTIONr_bond_other_d0.0020.022334
X-RAY DIFFRACTIONr_angle_refined_deg1.5921.963537
X-RAY DIFFRACTIONr_angle_other_deg1.17435435
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4545308
X-RAY DIFFRACTIONr_chiral_restr0.0910.2381
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022855
X-RAY DIFFRACTIONr_gen_planes_other0.0120.02544
X-RAY DIFFRACTIONr_nbd_refined0.2240.2634
X-RAY DIFFRACTIONr_nbd_other0.2390.22642
X-RAY DIFFRACTIONr_nbtor_other0.0870.21382
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.2157
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2450.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2690.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2780.213
X-RAY DIFFRACTIONr_mcbond_it0.8731.51536
X-RAY DIFFRACTIONr_mcangle_it1.5522494
X-RAY DIFFRACTIONr_scbond_it2.38131074
X-RAY DIFFRACTIONr_scangle_it3.7124.51043
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection
Rfree0.404 235
Rwork0.416 2815
all-3050

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